7α-Hydroxyacetyl and 7α-Hydroperoxyacetyl-substituted steroid compounds

ABSTRACT

The present invention involves intermediates, including a 7α-substituted steroid (II), 
                         
and processes which are used to prepare eplerenone, a useful pharmaceutical agent.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 10/392,833 filed Mar. 21, 2003 now U.S. Pat. No. 7,235,655, whichclaims the benefit of the following U.S. provisional patentapplications: Ser. No. 60/366,784, filed Mar. 22, 2002, Ser. No.60/411,874, filed Sep. 19, 2002, and Ser. No. 60/425,596, filed Nov. 12,2002, under 35 U.S.C. §119(e)(i), all of which are hereby incorporatedby reference in their entireties.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention includes a process for the transformation of a3-enol ether Δ^(3,5)-steroid to the corresponding Δ^(4,6)-3-ketalsteroid (I-P).

The present invention includes a process for the transformation of aΔ^(4,6)-3-keto steroid or ketal thereof (I), to the correspondingΔ⁴-3-ketosteroid-7α-carboxylic acid (VI).

The present invention also includes a novel processes and novelintermediates to produce the pharmaceutically useful compoundeplerenone.

Further, the invention includes processes for transformation of11α-hydroxy-17-lactone (CI) or 11α-hydroxy steroids (CIV) to thecorresponding Δ⁹⁽¹¹⁾-17-lactone (CII) or Δ⁹⁽¹¹⁾-steroids (CV) using aN-fluoroalkylamine reagents (CVI).

2. Description of the Related Art

It is known to transform 3-keto-Δ^(4,6)-steroids into the correspondingsteroidal Δ^(4,6)-3-ketals by acid-catalyzed ketalization. Yields aremoderate and double bond deconjugation can be competitive. For example,Δ^(4,6)-cholestadiene-3-one-3-cycloethyleneketal was prepared byketalization of Δ^(4,6)-cholestadien-3-one in 64% yield, see J. Org.Chem. 26, 2549 (1961). Also,17β-hydroxyandrosta-4,6-dien-3-one-3-cycloethyleneketal was prepared byketalization of 6-dehydrotestosterone in 55% crude yield, see J. Am.Chem. Soc., 86, 2183 (1964). The steroidal Δ^(4,6)-3-ketals (I-P) can beused as starting materials in the process to prepare eplerenone.

J. Org. Chem. 29, 601 (1964) reports that Δ^(3,5)-alkoxy steroids reactwith DDQ in the presence of water to give the correspondingΔ^(4,6)-3-keto steroids. The process of the present invention reactsΔ^(3,5)-3-alkoxy steroids (3-alkyl enol ether) with DDQ in the presenceof an alcohol under essentially anhydrous conditions to give theΔ^(4,6)-3-ketal steroid (I-P). In addition, the prior art methods ofproducing the Δ^(4,6)-3-ketal steroid (I-P) uses two steps,6-dehydrogenation of an enol ether to a Δ^(4,6)-3-keto steroid followedby ketalization whereas the present invention it a one step reaction.

Eplerenone, also known as epoxymexrenone, is a useful pharmaceuticalagent and chemically is9α,11α-epoxy-17β-hydroxypregn-4-en-3-one-7α,21-dicarboxylic acid,γ-lactone, methyl ester.

International Publication WO98/25948 of PCT application PCT/US97/23090discloses eplerenone and many different process to prepare eplerenone.In particular, see schemes 1 thru 10.

U.S. Pat. No. 4,874,754 discloses 19-nor steroids with 7α-arylsubstitution. The 7α-aryl substituent included a number of groupsincluding phenyl, thienyl, furyl, thiazolyl, pyrrolyl, oxazolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isothiazolyl andisoxazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl.Regardless of which group was used, the 19-nor compounds hadantiproliferative, anti-estrogenic and/or estrogenic properties and arenot useful intermediates to eplerenone because there are no practicalmethods for installing the 19-methyl group into 19-nor steroids. The7α-substituted steroids (II) of the present invention, areintermediates, not end products and do not have estrogenic propertiesbecause they are not 19-nor steroids.

U.S. Pat. No. 4,502,989 discloses a number of Δ¹¹-steroidal-γ-lactonesmany of which are substituted in the 7α-position which have aldosteroneantagonist activity. The 7α-substitution is 6α,7α-methylene-,7α-trimethylacetylthio-, 7α-acetylthio- and 7α-benzoythio-, see claim 1.These compounds differ from the compounds of the invention in that theC-ring double bond is Δ¹¹- and the 7α-substitutents are such that thecompounds cannot be used in the same way as the 7α-substituted steroids(II).

Het., 25, 399 (1987) and Bull. Soc. Chim. Fr. 131, 900 (1994) disclosethe use of boron trifluoride diethyl etherate to catalyze conjugateaddition of non-steroidal 2-methylfuran to α,β-unsaturated ketones inethanol/nitromethane. The process of the present invention, involvessteroidal furans. In addition, the enone substrates in Het., 25, 399(1987) and Bull. Soc. Chim. Fr. 131, 900 (1994) do not containstereocenters, so the issue of stereocontrol does not arise.

Methods for conjugate addition of carbon nucleophiles to9(11)-saturated-Δ^(4,6)-3-keto steroids to give9(11)-saturated-7α-substituted steroids stereoselectively are known. J.Am. Chem. Soc., 94, 4654 (1972) discloses conjugate addition of carbonnucleophiles to 9(11)-saturated-Δ^(4,6)-3-keto steroids to give9(11)-saturated-7α-substituted steroids stereoselectively. Tet, 49, 9955(1993) and Tet. Lett., 29, 1533 (1988) disclose stereoselective additionof allyltrimethylsilane to canrenone (titanium tetrachloride, methylenechloride, −78°) to give a mixture of two, difficult-to-separate products(7α-allyl-canrenone and the corresponding 6α,7α-fused silylcyclopentane)in poor yields (43-73% and 7-15%, respectively). Note that in thesecases the steroid substrate is 9(11) saturated. All attempts to applythese methods or similar methods to 9(11) unsaturated steroid substrateshave failed, due to lack of stereocontrol. For example, U.S. Pat. No.4,559,332, Example 7, discloses that trimethylsulfoxonium iodide adds toΔ⁹⁽¹¹⁾-canrenone (I) using sodium hydride in DMSO at room temperature togive exclusively 6β,7β-methylene-Δ⁹⁽¹¹⁾-canrenone. Also, nitromethaneadds to Δ⁹⁽¹¹⁾-canrenone (I) in tetramethylguanidine at room temperatureover 7.5 hrs.) to give exclusively the 7β stereoisomer(7β-nitromethyl-Δ⁹⁽¹¹⁾-6,7-dihydrocanrenone.

Helv. Chim. Acta, 80, 566 (1997) and U.S. Pat. No. 4,559,332 disclosethat reaction of Δ⁹⁽¹¹⁾-canrenone with diethylaluminum cyanide to give7α-cyano-Δ⁹⁽¹¹⁾-6,7-dihydrocanrenone, but the crude product is describedas a “brownish amorphous residue” that “was filtered through silica gelyielding amorphous” semipurified product “which was used without furtherpurification in the next step.” The ratio of 7-α to 7-β epimers is notdisclosed.

J. Am. Chem. Soc. 79, 3120 (1957), J. Am. Chem. Soc. 82, 6136 (1960),and J. Org. Chem. 27, 1192 (1962) disclose degradation of non-steroidalenediones to carboxylic acids through alkoxyhydroperoxide intermediatesand not hydroxyhydroperoxide intermediates. The process of the presentinvention involves steroidal enediones.

The oxidative opening of furans to carboxylic acids, or carboxylic acidderivatives, by direct ozonolysis is known. However, the yields areusually quite poor. J. Org. Chem., 61, 9126 (1996), reported that a2,5-disubstituted furan on ozonization underwent partial cleavage to anenol acetate rather than complete cleavage to the carboxylic acid. Het,34, 895 (1992) reported direct ozonization of a 2-substituted furangave, after esterification, the methyl ester in 59% yield. J. Am. Chem.Soc. 101, 259 (1979) reported direct ozonization of a 2-substitutedfuran gave, after esterification, the methyl ester in 55% yield. J. Am.Chem. Soc., 107, 7762 (1985) reported direct ozonization of a2-sugar-substituted furan gave, after borane reduction, the primaryalcohol in 50% yield. Tet. Lett., 34, 7323 (1993) reported directozonization of a 2-substituted furan gave, after esterification, themethyl ester in 60% yield. Carb. Res., 150, 163 (1986) reported directozonization of a 2-sugar-substituted furan afforded, after reductionwith triphenylphosphine followed by lithium aluminum hydride, theprimary alcohol in 11% yield. Tet. Lett., 22, 141 (1981) reported directozonization of a 2-substituted furan gave, after oxidative workup, thecarboxylic acid in approximately 30% yield. J. Am. Chem. Soc., 109, 2082(1987) reported direct ozonization of a 2-substituted furan gave, afteresterification, the methyl ester in 77% yield. Tet. Lett., 39, 7013(1998) reported direct ozonization of a 2-substituted furan gave, afteresterification, the methyl ester in 78%-87% yield. J. Org. Chem., 54,2085 (1989) reported direct ozonization of two 2-substituted furansgives the carboxylic acid in 89-95% yield, however, in this study, the2-substituted furans were very simple (i.e., they did not contain anyreactive functional group other than the furan). There is no disclosuresof a two step furan opening and then oxidative cleavage to thecarboxylic acid which results in high yields.

J. Org. Chem. 63, 7505 (1998) discloses the use of dibromatin, sodiumbicarbonate and aqueous acetone to open non-steroidal furans to produceenediones. The process of the present invention involves steroidalfurans.

Chem. Let., 1771 (1983) discloses the use of hydrochloric acid in etherto catalyze the isomerization of non-steroidal cis-enediones totrans-enediones. The process of the present invention involves steroidalenediones.

J. Am. Chem. Soc., 79, 3120 (1957), J. Am. Chem. Soc., 82, 6136 (1960)and J. Org. Chem., 27, 1192 (1962) disclose the degradation of enedionesto carboxylic acids through alkoxyhydroperoxide intermediates by use ofozone and an oxidatively cleaving agent. The yields are not particularlyhigh. For example, the yield of benzoic acid fromtrans-dibenzoylethylene was 54%. Following this process,methoxyhydroperoxide (IV-OOH) (where R_(7.2)=—CH₃) gave a 65.2/34.8mixture of the desired carboxylic acid (VI) and α-ketomethylester where(R_(b)═OMe). The α-ketomethyl ester can not be transformed to aneplerenone useful compound and its production makes this process notcommercially useful. By contrast, in the process of this invention, theenedione (III) is degraded to the carboxylic acid (VI) through thehydroxyhydroperoxide intermediate (IV-OOH, where R₇₋₂=—H), whichsurprisingly rearranges to the desired carboxylic acid (VI) in nearlyquantitative yield. The process of the present invention uses ozone, ahydroperoxy-deoxygenating agent and then a oxidatively cleaving agent toavoid production of the α-ketomethylester and obtain increased yields.

Drugs of the Future, 24, 488 (1999) discloses conversion of the5,7-lactone (VII) to the corresponding methyl ester (VIII) by treatmentwith “methyl iodide in basic medium,”. The process of the presentinvention for methylation is a sequential process.

International Publication WO98/25948 generically discloses(5,7)-17-bislactones and 3 protected forms.

International Publication WO98/25948 discloses the transformation of asteroidal 7α-acid to the (5,7)-17-bislactone. This process requires anorthoester. The process of the present invention does not require anorthoester.

International Publication WO98/25948 discloses the transformation ofa-(5,7)-17-bislactone to the corresponding 7α-CO—OCH₃ in one step. Thepresent invention uses two steps but obtains better yields and consumesless reagent.

Eplerenone is9(11)α-epoxy-17β-hydroxypregn-4-en-3-one-7α,21-dicarboxylic acid,γ-lactone, methyl ester and as such contains a 7α-carbomethoxysubstituent. From the standpoint of production, a major difficulty inthe production of eplerenone is introduction of the 7α-carbomethoxysubstituent. The present invention includes an improved proved processfor the introduction of the 7α-substitutent.

It is known that a carboxylic acid can be obtained from a (substituted)furan in one step by ozonolysis. However, the yields are quite low.Further, it is known that furans can be opened to enediones. It is alsoknown that enediones can be oxidized to carboxylic acids.

Bulletin of the Chemical Society of Japan, 52, 3377-3380 (1979)discloses that N-(1,1,2,2,3,3,3)hexafluoropropyldiethylamine, “Ishikawareagent” is used to replace a hydroxyl group with a fluorine atom oreliminate a hydroxyl group to an olefin. With cyclohexanol, a simplemonocyclic system, the elimination product olefin was 78%. However, whenthe “Ishikawa reagent” was applied to a steroid, cholesterol, thecorresponding fluoro compound cholesteryl fluoride was obtained in 83%yield; no elimination product was reported.

J. Org. Chem., 2187-2195(1964) discloses the reaction of11α-hydroxypregn-4-ene-3,20-dione with2-chloro-1,1,2-trifluorotriethylamine to give the elimination product,pregna-4,9(11)-diene-3,20-dione, in 86% yield. The process of thepresent invention does, not use 2-chloro-1,1,2-trifluorotriethylaminealso known as Yarovenko reagent. Further, use of2-chloro-1,1,2-trifluorotriethylamine is a problem because it is notstable enough to make scale up practicable. In addition, it is derivedfrom a chlorofluorocarbon and is not environmentally sound.

Tetrahedron Letters, 1065-1069 (1962) also discloses the reaction of11α-hydroxypregn-4-ene-3,20-dione with2-chloro-1,1,2-trifluorotriethylamine to give the elimination product,pregna-4,9(11)-diene-3,20-dione.

Steroids, 29, 2187 (1964) discloses the reaction of steroidal alcoholswith 2-chloro-1,1,2-trifluorotriethylamine to replace the hydroxyl groupwith fluorine. The present invention does not use2-chloro-1,1,2-trifluorotriethylamine, nor does it replace a hydroxylgroup with a fluorine atom.

J. Fluorine Chem., 109, 25-31 (2001) describes and compares the use of1,1,2,2-tetrafluoroethyl-N,N-dimethylamine as well as Yarovenko-Rakshaand Ishikawa reagent as fluorinating and dehydrating agents. While thedocument discloses examples of elimination reactions in both aliphaticand cyclic systems, the primary use is as a fluorinating agent. The onlysteroid example was the reaction of1,1,2,2-tetrafluoroethyl-N,N-dimethylamine with cholesterol whichproduced a product with fluorine at the C-3 position of cholesterol.

SUMMARY OF INVENTION

Disclosed is a process for the preparation of a Δ^(4,6)-ketal of formula(I-P)

where R₃₁ and R₃₂ are

(1) the same or different and are C₁-C₃ alkyl, and

(2) taken with the attached —O—C—O— to form a cyclic ketal of 5 or 6atoms of the formula—(CH₂)—(CR₃₃R₃₄)_(n1)—(CH₂)—

-   -   where n₁ is 0 or 1;    -   where R₃₃ and R₃₄ are the same or different and are        -   —H,        -   C₁-C₃ alkyl,            which comprises

(1) contacting a Δ^(3,5)-3-enol ether of formula (Alkyl enol ether)

where R³ is

C₁-C₃ alkyl,

CH₃—CO—,

φ—CO— or

R_(Si-1)R_(Si-2)R_(Si-3)Si— where R_(Si-1), R_(Si-2) and R_(Si-3) arethe same or different and are C₁-C₄ alkyl; with a hydride abstractor andan alcohol selected from the group consisting of alcohols 10′ of theformula:

(a) R₃₁—OH, where R₃₁ is a is defined above,

(b) R₃₂—OH, where R₃₂ is as defined above,

(c) HO—(CH₂)—(CR₃₃R₃₄)_(n1)—(CH₂)—OH where n₁; R₃₃ and R₃₄ are asdefined above,

(d) HO—CH₂—CH₂—OH.

Also disclosed is a 7α-substituted steroid of formula (II)

where

(I) R₁₃ is ═O; R₄ is R₄₋₁:R₄₋₂ where one of R₄₋₁ and R₄₋₂ is —H and theother of R₄₋₁ and R₄₋₂ is taken together with R₅ to form a second bondbetween the carbon atoms to which they are attached; R₆ is —H:—H;

(II) R₃ is R₃₋₃:R₃₋₄ and R₄ is R₄₋₃:R₄₋₄ where one of R₃₋₃ and R₃₋₄ is—O—R₃₁ where R₃₁ is C₁-C₃ alkyl, the other of R₃₋₃ and R₃₋₄ is takentogether with one of R₄₋₃ and R₄₋₄ to form a second bond between thecarbon atoms to which they are attached, and the other of R₄₋₃ and R₄₋₄is —H; R₆ is R₆₋₃:R₆₋₄ where one of R₆₋₃ and R₆₋₄ is taken together withR₅ to form a second bond between the carbon atoms to which they areattached and the other of R₆₋₃ and R₆₋₄ is —H;

(III) R₃ is α-R₃₋₅:β-R₃₋₆ where R₃₋₅ is —O—R₃₁ and R₃₋₆ is —O—R₃₂ whereR₃₁ and R₃₂ are the same or different and are selected from the groupconsisting of

-   -   C₁-C₃ alkyl and

R₃₁ and R₃₂ are taken with the attached —O—C—O— to form a cyclic ketalof 5 or 6 atoms of the formula—(CH₂)—(CR₃₃R₃₄)_(n1)—(CH₂)—

where n₁ is 0 or 1;

where R₃₃ and R₃₄ are the same or different and are —H and C₁-C₃ alkyl;R₄ is —H:—H; R₆ is R₆₋₅:R₆₋₆ where one of R₆₋₅ and R₆₋₆ is takentogether with R₅ to form a second bond between the carbon atoms to whichthey are attached and the other of R₆₋₅ and R₆₋₆ is —H;

(IV) R₃ is α-R₇:β-R₃₋₈ where R₃₋₇ is —O—R₃₁ and R₃₋₈ is —O—R₃₂ where R₃₁and R₃₂ are as defined above; R₄ is R₄₋₇:R₄₋₈ where one of R₄₋₇ and R₄₋₈is taken together with R₅ to form a second bond between the carbon atomsto which they are attached and the other of R₄₋₇ and R₄₋₈ is —H; R₆ is—H:—H;

where R₇₋₁ is a molecular fragment of the formula (-A1)

or of the formula (-A2)

where X₁ is:

-   -   —S—,    -   —O— or    -   —NX₁₋₁— and where X₁₋₁ is:        -   —H,        -   C₁-C₄ alkyl,        -   —CO—OX₁₋₂ where X₁₋₂ is C₁-C₄ alkyl or —CH₂—φ,        -   —CO—X₁₋₂ where X₁₋₂ is as defined above,        -   —CO—φ where is substituted in the position with —CO—O—(C₁-C₄            alkyl),        -   —SO₂—(C₁-C₃ alkyl),        -   —SO₂—φ where φ is optionally substituted with 1 or 2            -   C₁-C₄ alkyl,            -   C₁-C₄ alkoxy;

where R_(b) is selected from the group consisting of

-   -   —H,    -   C₁-C₄ alkyl or    -   phenyl optionally substituted with 1 or 2        -   C₁-C₄ alkyl,        -   C₁-C₄ alkoxy,

where R_(c) is selected from the group consisting of:

-   -   —H,    -   C₁-C₄ alkyl,    -   C₁-C₄ alkoxy,    -   —O—Si(R)₃ where the R's are the same or different and are —H,        C₁-C₄ alkyl, —φ, C₁-C₄ alkoxy and —OH,    -   —F, —Cl, —Br, —I,    -   —CO—OCH₃ and    -   —CO—R_(c-1) where R_(c-1) is C₁-C₄ alkyl or —φ;

where R_(d) is selected from the group consisting of

-   -   —H,    -   —C≡N,    -   C₁-C₁₀ alkyl;    -   —C₁-C₄ alkoxy;    -   —CH₂—OR_(d-1) where R_(d-1) is —H or C₁-C₄ alkyl,    -   —CH₂—N(R_(d-6))₂ where the two R_(d-6) are the same or different        and are:        -   C₁-C₄ alkyl,        -   —φ,        -   —CO—R_(d-6a) where R_(d-6a) is C₁-C₄ alkyl or —φ,    -   —CH₂—O—CO—R_(d-1) where R_(d-1) is as defined above,    -   —CH(OR_(d-1))₂ where R_(d-1) is as defined above and where the        two R_(d-1) taken together are;        -   —CH₂—CH₂—,        -   —CH₂CH₂—CH₂—,        -   —CH₂—C(CH—)₂—CH₂—,    -   —CH(—O—CO—R_(d-1))₂ where R_(d-1) is as defined above,    -   —Si(R)₃ where R is as defined above,    -   —O—Si(R)₃ where R is as defined above,    -   —Sn(R_(b-1))₃ where R_(b-1) is as defined above,    -   —S—R_(d-5) where R_(d-5) is C₁-C₄ alkyl or —φ,    -   —N(R_(d-6))₂ where R_(d-6) is as defined above,

where R_(c) and R_(d) taken together with the atoms to which they areattached to form.

where E₁ are the same or different and are:

-   -   —H,    -   C₁-C₄ alkyl,    -   —F, —Cl, —Br, —I,    -   —OE₁₋₁ where E₁₋₁ is:        -   —H,        -   C₁-C₄ alkyl,        -   —φ or        -   —SiE₁₋₂E₁₋₃E₁₋₄ where E₁₋₂, E₁₋₃ and E₁₋₄ are the same or            different and are C₁-C₄ alkyl or C₁-C₄ alkoxy,    -   —S-E₁₋₅ where E₁₋₅ is C₁-C₄ alkyl or —φ,    -   —S—(O)₁₋₂-E₁₋₅ where E₁₋₅ is as defined above,    -   —N(R_(d-6))₂ where the two R_(d-6) are the same or different and        are as defined above,    -   —P(O)(O-E₁₋₁)₂ where E₁₋₁ is as defined above,    -   —Si(R)₃ where R is as defined above;        —CE₁=M  (-B)

where E₁ is as defined above and

where M is:

-   -   (1) ═O,    -   (2)=N-E₂ where E₂ is selected from the group consisting of        -   —H        -   C₁₋₄ alkyl,        -   C₁-C₄-alkenyl containing 1 or 2 double bonds,        -   C₁-C₄ alkynyl containing 1 triple bond,        -   —CO—OE₂₋₁ where E₂₋₁ is —H or C₁-C₄ alkyl,        -   —C(E₂₋₁)₂-OE₂₋₂ where E₂₋₁ are the same or different and are            as defined above and where E₂₋₂ is            -   C₁-C₄ alkyl,            -   —φ or            -   —Si(R)₃ where the three R are the same or different and                are defined above,        -   —OE₂₋₂ where E₂₋₂ is as defined above,        -   —S-E₂₋₃ where E₂₋₃ is C₁-C₄ alkyl or —φ,        -   —S—(O)₁₋₂-E₂₋₃ where E₂₋₃ is as defined above,        -   —N(R_(d-6))₂ where the two R_(d6) are the same or different            and are as defined above;        -   —Si(R)₃ where the three R are as defined above;    -   (3) ═C(E₂)₂ where the E₂ are the same or different and are as        defined above,

where E₁ and E₂ are taken together with the atoms to which they areattached to form a ring of 5 thru 7 members, optionally containing 3thru 5

-   -   —O—,    -   —S—,    -   —N═,    -   —NX₁₋₁— where X₁₋₁ is as defined above,    -   —CE₂=where E₂ is as defined above,    -   —C(R_(b))₂— where R_(b) is as defined above, and optionally        containing 1 or 2 additional double bonds;        —C≡C-E₂  (-C)

where E₂ is as defined above;—CH₂—CH═CH₂  (-D1)—CH═C═CH₂  (-D2)—CH₂—C≡C—H  (-D3)

where R₉ is:

-   -   (1) —H,    -   (2) —OH,    -   (3) —O-(HYDROXY PROTECTING GROUP) where HYDROXY PROTECTING GROUP        is selected from the group consisting of        -   —Si(—CH₃)₃,        -   —Si(—CH₂—CH₃)₃,        -   —CO—CH₃,        -   —CO—H and        -   —SiH(CH₃)₂,    -   (4) —F;

where R₁₁ is:

-   -   (1) ═O,    -   (2) —H:—H,    -   (3) α-R₁₁₋₁:β-R₁₁₋₂ where R₁₁₋₁ is:        -   (a) —H,        -   (b) —O—R₁₁₋₃ where R₁₁₋₃ is:            -   (i) —H,            -   (ii) a HYDROXY PROTECTING GROUP) where HYDROXY                PROTECTING GROUP is as defined above, and where R₁₁₋₂                is:        -   (a) —H,        -   (b) O—R₁₁₋₄ where R₁₁₋₄ is:            -   (i) —H,            -   (ii) a HYDROXY PROTECTING GROUP) where HYDROXY                PROTECTING GROUP is as defined above, with the proviso                that one of R₁₁₋₁, and R₁₁₋₂ must be —H,    -   (4) R₁₁₋₅:R₁₁₋₆ where one of R₁₁₋₅ or R₁₁₋₆ and R₉ are taken        together with R₉ to form a second bond between C-9 and C-11 and        the other of R₁₁₋₅ or R₁₁₋₆ is —H,    -   (5) α-R₁₁₋₇:β-R₁₁₋₈ where R₁₁₋₇ and R₉ are taken together with        —O— to form an epoxide between C-9 and C-11 and R₁₁₋₈ is —H;

where R₁₇ is:

-   -   (1) ═O;    -   (2) α-R₁₇₋₁:β-R₁₇₋₂ where R₁₇₋₁, is:        -   (a) —H,        -   (b) —C≡C—H,        -   (c) —C≡N,        -   (d) —C≡C—CH₂—O—R₁₇₋₁₋₁ where R₁₇₋₁₋₁ is selected from the            group consisting of            -   (i) —H,            -   (ii) —Si(R₁₇₋₁₋₂)₃ where R₁₇₋₁₋₂ are the same or                different and are C₁-C₄ alkyl,            -   (iii) 1-ethoxyethyl,            -   (iv) 2-tetrahydropyranyl,        -   (e) —C≡C—CH₂—O-(HYDROXY PROTECTING GROUP), where HYDROXY            PROTECTING GROUP is as defined above,        -   (f) —CH₂—CH₂—CH₂—OH,        -   (g) —CH₂—CH₂—CH₂—O-(HYDROXY PROTECTING GROUP), where HYDROXY            PROTECTING GROUP is as defined above,        -   (h) CH₂—CH₂—CO—O⁻ and where R₁₇₋₂ is —OH;    -   (3) α-R₁₇₋₃:β-R₁₇₋₄ where R₁₇₋₄ is OH and where R₁₇₋₄ is:        -   (a) —CO—CH₃,        -   (b) CO—CH₂—OH,        -   (c) —CO—CH₂—O—CO—(CH₂)₀₋₃—CH₃;    -   (4) α-R₁₇₋₅:β-R₁₇₋₆ where R₁₇₋₅ and R₁₇₋₄ are taken with the        attached carbon atom to form a three member epoxide containing        O—CH₂— where the attachment of the —O is at R₁₇₋₆ in the        β-orientation and the attachment of the CH₂— is at R₁₇₋₆ in the        α-orientation;    -   (5) α-R₁₇₋₇:β-R₁₇₋₈ where R₁₇₋₇ and R₁₇₋₈ are taken with the        attached carbon atom to form a five member lactone containing        —O—CO—CH₂—CH₂— where the attachment of the CH₂— is at R₇₁₋₇ in        the α-orientation and the attachment of the —O is at R₁₇₋₈ in        the β-orientation;    -   (6) —O—CH(OR₁₇₋₉)—CH₂—CH₂ . . . where the bond from the oxygen        (—O) is one of the four bonds at C-17 in the β-configuration and        the bond from the methylene group (CH₂ . . . ) is another of the        four bonds at C-17 in the α-configuration to form a 5 member        heterocycle containing one oxygen atom, where R₁₇₋₉ is —H or        C₁-C₃ alkyl;    -   (7) α-R₁₇₋₁₁:β-R₁₇₋₁₂ where R₁₇₋₁₀ is —(CH₂)₁₋₂—CH═CH₂ and        R₁₇₋₁₂ is —OH.

Further disclosed is a cis enedione of the formula (III-cis)

and a trans enedione of the formula (III-trans)

where

(I) R₃ is ═O; R₄ is R₄₋₁:R₄₋₂ where one of R₄₋₁ and R₄₋₂ is —H and theother of R₄₋₁ and R₄₋₂ is taken together with R₅ to form a second bondbetween the carbon atoms to which they are attached; R₆ is —H:—H;

(III) R₃ is α-R₃₋₅:β-R₃₋₆ where R₃₋₅ is —O—R₃₁ and R₃₋₆ is —R₃₂ whereR₃₁ and R₃₂ are the same or different and are selected from the groupconsisting of

-   -   C₁-C₃ alkyl and    -   R₃₁ and R₃₂ are taken with the attached —O—C—O— to form a cyclic        ketal of 5 or 6 atoms of the formula        —(CH₂)—(CR₃₃R₃₄)_(n1)—(CH₂)—.

where n₁ is 0 or 1;

where R₃₃ and R₃₄ are the same or different and are +H and C₁-C₃ alkyl;R₄ is —H:—H; R₆ is R₆₋₅:R₆₋₆ where one of R₆₋₅ and R₆₋₆ is takentogether with R₅ to form a second bond between the carbon atoms to whichthey are attached and the other of R₆₋₅ and R₆₋₆ is —H; (IV)

R₃ is α-R₃₋₇:β-R₃₋₈ where R₃₋₇ is —O—R₃₁ and R₃₋₈ is —R₃₂ where R₃₁ andB₃₂ are as defined above; R₄ is R₄₋₇:R₄₋₈ where one of R₄₋₇ and R₄₋₈ istaken together with R₅ to form a second bond between the carbon atoms towhich they are attached and the other of R₄₋₇ and R₄₋₈ is —H; R₆ is—H:—H;

where R₉, R₁₁ R₁₇ are as defined above;

where R_(b) is selected from the group consisting of

-   -   —H,    -   C₁-C₄ alkyl or    -   phenyl optionally substituted with 1 or 2        -   C₁-C₄ alkyl,        -   C₁-C₄ alkoxy,

where R_(c) is selected from the group consisting of:

-   -   —H,    -   C₁-C₄ alkyl,    -   C₁-C₄ alkoxy,    -   —O—Si(R)₃ where the R's are the same or different and are —H,        C₁-C₄ alkyl, —φ, C₁-C₄ alkoxy and —OH,    -   —F, —Cl, —Br, —I,    -   —CO—OCH₃ and    -   —CO—R_(c-1) where R_(c-1) is C₁-C₄ alkyl or —φ;

where R_(d) is selected from the group consisting of

-   -   —H,    -   —C≡N,    -   C₁-C₁₀ alkyl;    -   C₁-C₄ alkoxy;    -   —CH₂—OR_(d-1) where R_(d-1) is —H or C₁-C₄ alkyl,    -   —CH₂—N(R_(d-6))₂ where the two R_(d-6) are the same or different        and are:        -   C₁-C₄ alkyl,        -   —φ,        -   —CO—R_(d-6a), where R_(d-6a) is C₁-C₄ alkyl or —φ,    -   —CH₂—O—CO—R_(d-1) where R_(d-1) is as defined above,    -   —CH(OR_(d-1))₂ where R_(d-1) is as defined above and where the        two R_(d-1) taken together are:        -   —CH₂—CH₂—,        -   —CH₂—CH₂CH₂—,        -   —CH₂—C(CH₃—)₂—CH₂—,    -   —CH(—O—CO—R_(d-1))₂ where R_(d-1) is as defined above,    -   —Si(R)₃ where R is as defined above,    -   O—Si(R)₃ where R is as defined above,    -   —Sn(R_(b-1))₃ where R_(b-1) is as defined above,    -   —S—R_(d-5) where R_(d-5) is C₁-C₄ alkyl or —φ,    -   —N(R_(d-6))₂ where R_(d-6) is as defined above,

where R_(c) and R_(d) taken together with the atoms to which they areattached to form

where E₁ are the same or different and are:

-   -   —H,    -   C₁-C₄ alkyl,    -   —F, —Cl, —Br, —I,    -   —OE₁₋₁ where E₁₋₁ is:        -   —H,        -   C₁-C₄ alkyl,        -   —φ or        -   —SiE₁₋₂E₁₋₃E₁₋₄ where E₁₋₂, E₁₋₃ and E₁₋₄ are the same or            different and are C₁-C₄ alkyl or C₁-C₄ alkoxy,    -   —S-E₁₋₅ where E₁₋₅ is C₁-C₄ alkyl or —φ,    -   —S—(O)₁₋₂-E₁₋₅ where E₁₋₅ is as defined above,    -   —N(R_(d-4))₂ where the two R_(d-6) are the same or different and        are as defined above,    -   —P(O)(O-E₁₋₁)₂ where E₁₋₁ is as defined above,    -   —Si(R)₃ where R is as defined above.

Further disclosed is a hydroxy compound of formula (IV-OH)

and a hydroperoxy compound (IV-O—OH)

where R₃, R₄, R₅ and R₆ are as defined for the cis and trans enedione(III-cis) and (III-trans) and where R₉, R₁₁ R₁₇ and R_(b) are as definedabove and where R₇₋₂ is —H and C₁-C₄ alkyl optionally substituted withone or two —OH.

Disclosed is a biscarbonyl compound of the formula (V)

where R₃, R₄, R₅ and R₆ are as defined for the cis and trans enedione(III-cis) and (III-trans) and where R₉, R₁₁, R₁₇ and R_(b) are asdefined above.

Also disclosed is a cis oxyenedione of the formula (X-cis)

and a trans enedione of the formula (X-trans)

where R₃, R₄, R₅ and R₆ are as defined for the cis and trans enedione(III-cis) and (III-trans) and where R₉, R₁₁ R₁₇, R_(b), R_(c), and R_(d)are as defined above.

Further disclosed is a 7α-unsaturated steroid of formula (XIV)

where R₃, R₄, R₅ and R₆ are as defined for the cis and trans enedione(III-cis) and (III-trans) and where R₉, R₁₁ R₁₇, R_(b) and R_(d) are asdefined above.

Additionally disclosed is a 7α-preacid of the formula (XV)

where R₃, R₄, R₅, and R₆ are as defined for the cis and trans enedione(III-cis) and (III-trans) and where R₅, R₁₁ R₁₇ and R_(b), are asdefined above.

Disclosed is a process for the preparation of a 7α-substituted steroid(II) of the formula

where

(I) R₃ is ═O; R₄ is R₄₋₁:R₄₋₂ where one of R₄₋₁ and R₄₋₂ is —H and theother of R₄₋₁ and R₄₋₂ is taken together with R₅ to form a second bondbetween the carbon atoms to which they are attached; R₆ is —H:—H;

(II) R₃ is R₃₋₃:R₃₋₄ and R₄ is R₄₋₃:R₄₋₄ where one of R₃₋₃ and R₄ is—R₃₁ where R₃₁ is C₁-C₃ alkyl, the other of R₃₋₃ and R₃₋₄ is takentogether with one of R₄₋₃ and R₄₋₄ to form a second bond between thecarbon atoms to which they are attached, and the other of R₄₋₃, and R₄₋₄is —H; R₆ is R₆₋₃:R₆₋₄ where one of R₆₋₃ and R₆₋₄ is taken together withR₅ to form a second bond between the carbon atoms to which they areattached and the other of R₆₋₃ and R₆₋₄ is —H;

(III) R₃ is α-R₃₋₅:β-R₃₋₆ where R₃₋₅ is —O—R₃₁ and R₃₋₆ is O—R₃₂ whereR₃₁ and R₃₂ are the same or different and are selected from the groupconsisting of

-   -   C₁-C₃ alkyl and    -   R₃₁ and R₃₂ are taken with the attached —O—C—O— to form a cyclic        ketal of 5 or 6 atoms of the formula        —(CH₂)—(CR₃₃R₃₄)_(n1)—(CH₂)—

where n₁ is 0 or 1;

where R₃₃ and R₃₄ are the same or different and are —H and C₁-C₃ alkyl;R₄ is —H:—H; R₆ is R₆₋₅:R₆₋₆ where one of R₆₋₅ and R₆₋₆ is takentogether with R₅ to form a second bond between the carbon atoms to whichthey are attached and the other of R₆₋₅ and R₆₋₆ is —H;

(IV) R₃ is α-R₃₋₇:β-R₃, where R₃₋₇ is —O—R₃₁ and R₃₋₈ is —O—R₃₂ whereR₃₁ and R₃₂ are as defined above; R₄ is R₄₋₇:R₄₋₈ where one of R₄₋₇ andR₄₋₈ is taken together with R₅ to form a second bond between the carbonatoms to which they are attached and the other of R₄₋₇ and R₄₋₈ is —H;R₆ is —H:—H;

where R₇₋₁, R₉, R₁₁ and R₁₇, are as defined above; which comprises:

-   -   (1) contacting a Δ^(4,6)-3-keto steroid or ketal thereof (I) of        the formula

where

(I) R₃ is ═O; R₄ is R₄₋₁:R₄₋₂ where one of R₄₋₁ and R₄₋₂ is —H and theother of R₄₋₁ and R₄₋₂ is taken together with R₅ to form a second bondbetween the carbon atoms to which they are attached;

(I-ketal) R₃ is R₃₋₉:R₃₋₁₀ where R₃₋₉ is —O—R₃₁ and R₃₋₁₀ is O—R₃₂ whereR₃₁ and R₃₂ are the same or different and are selected from the groupconsisting of

-   -   C₁-C₃ alkyl and    -   R₃₁ and R₃₂ are taken with the attached —O—C—O— to form a cyclic        ketal of 5 or 6 atoms of the formula        —(CH₂)—(CR₃₃R₃₄)_(n1)—(CH₂)—

where n₁ is 0 or 1;

where R₃₃ and R₃₄ are the same or different and are —H and C₁-C₃ alkyl;R₄ is R₄₋₉:R₄₋₁₀ where one of R₄₋₉ and R₄₋₁₀ is taken together with R₅to form a second bond between the carbon atoms to which they areattached and the other of R₄₋₉ and R₄₋₁₀ is —H;

where R₉, R₁₁, and R₁₇ are as defined above, with an adduct selectedfrom compounds (a) of the formula (A)

where X₁, R_(b), R_(c) and R_(d) are as defined above, and

where R_(a) is selected from the group consisting of —H, -ZnL, —BL,—SiL₃, —SnL₃, —Cu, —CuL, —AlL₂, —HgL, —Ag, —MgL, —Li and —COOH, where Lis OH, C₁-C₄ alkyl, —F, —Cl, —Br, —I, —CN, —O(C₁-C₃ alkyl), 2-thienyl,(CH₃)₂C(O—)—C(O—)—C(CH₃)₂ and

(b) of the formula (A′)R_(b)—CO—CHR_(b)—CHR_(c)—CO—R_(d)  (A′)where R_(b), R_(c) and R_(d) are as defined above;

(c) of the formula (A″)

where R_(e) is:

-   -   C₁-C₄ alkyl,    -   —CO—(C₁-C₄ alkyl or —φ),    -   —Si(R)₃ where B is as defined above and where X₁, R_(b), R_(c)        and R_(d) are as defined above;

(d) of the formula (B)R_(a)—CE₁=M  (B)

-   -   where R_(a), E₁ and M are as defined above;

(e) of the formula (C)R_(a)—C≡C-E₂  (C)

-   -   where R_(a) and E₂ are as defined above;

(f) of the formulas (D1, D2 and D3)R_(a)—CH₂—CH═CH₂  (D1)R_(a)—CH═C═CH₂  (D2)R_(a)—CH₂—C≡C—H  (D3)where R_(a) is as defined above, in the presence of:

(1) a Lewis Acid,

(2) a proton acid with a pK_(a) of <about 5 or

(3) a salt of a secondary amine of the formula

where:

-   -   R_(S-2) is —H, C₁-C₄ alkyl, —φ, and —CH₂—φ;    -   R_(S-3) is —H, C₁-C₄ alkyl;    -   R_(S-4) is —H, C₁-C₄ alkyl, —φ;    -   R_(S-5) is —H, C₁-C₄ alkyl, —φ;        and

where

-   -   R_(S-2) is —H, C₁-C₄ alkyl, —φ, and —CH₂—φ;    -   R_(S-4) is —H, C₁-C₄ alkyl, —φ;    -   R_(S-5) is —H, C₁₋₄ alkyl, —φ;        with an acid of pK_(a) of <about 2.

Also disclosed is a process for purifying a 7α-substituted steroid offormula (II) where R₃, R₄, R₅ and R₆ are as defined for the7α-substituted steroid (II) and where R₇₋₁, R₉, R₁₁ and R₁₇ are asdefined above; which comprises:

(1) crystallizing 7α-substituted steroid (II) which contains greaterthan 5% of 7β-isomer from a solvent selected from the group consistingof ethyl acetate, propyl acetate and butyl acetate.

Further disclosed is a process for the preparation of a cis-enedione offormula (III-cis)

where R₃, R₄, RE and R₆ are as defined for the cis and trans enedione(III-cis) and (III-trans) and where R₇₋₁, R₇₋₂, R₉, R₁₁, R₁₇, R_(b),R_(c), R_(d) are as defined above; which comprises:

(1) contacting a 7α-substituted steroid of formula (II)

where R₃, R₄, R₅, R₆, R₇₋₁, R₉, R₁₁ and R₁₇ are as defined above; withan agent selected from the group consisting of:

-   -   (a) a halogenating agent in the presence of water and a base        whose conjugate acid has a pK_(a) of >about 8,    -   (b) an oxygen donating agent,    -   (c) electrochemical oxidation,    -   (d) a quinone in the presence of water or    -   (e) nonquinone oxidants.

Additionally disclosed is a process for the preparation of atrans-enedione of formula (III-trans)

where R₃, R₄, R₅ and R₆ are as defined for the cis and trans enedione(III-cis) and (III-trans) and where R₉, R₁₁, R₁₇, R_(b), R_(c) and R_(d)are as defined above; which comprises:

(1) contacting a cis-enedione of formula (III-cis)

where R₃, R₄, R₅, R₆, R₉, R₁₁, R₁₇, R_(b), R_(c) and R_(d) are asdefined above with an isomerization catalyst selected from the groupconsisting of:

(a) a strong acid of pK_(a) of >about 2;

(b) a tertiary amine whose conjugate acid has a pK_(a)>about 8 and

(c) salt of a tertiary-amine whose conjugate acid has a pK_(a)>about 8,

(d) I₂,

(e) (C₁-C₄)₃P,

(f) φ₃P,

(g) heating to about 80°.

Disclosed is a process for the preparation of a hydroxy compound offormula (IV-OH)

or a hydroperoxy compound of formula (IV-OOH)

or a biscarbonyl compound of formula (V)

or a carboxylic acid of formula (VI)

or a mixture thereof, where R₃, R₄, R₅ and R₆ are as defined for the cisand trans enedione (III-cis) and (III-trans) and where R₇₋₂, R₉, R₁₁,R₁₇, R_(b) are as defined above; which comprises:

(1) contacting a cis-enedione of the formula (III-cis)

or a trans-enedione of the formula (III-trans)

or a mixture thereof, where R₃, R₄, R₅, R₆, R₉, R₁₁, R₁₇, R_(b), R_(c)and R_(d) are as defined above, with ozone in the presence of an alcoholof the formula R₇₋₂—OH, where R₇₋₂ is as defined above.

Also disclosed is a process for the preparation of a hydroxy-compound offormula (IV-OH)

where R₃, R₄, R₅ and R₆ are as defined for the cis and trans enedione(III-cis) and (III-trans) and where R₇₋₂, R₉, R₁₁, R₁₇ and R_(b) are asdefined above; which comprises:

(1) contacting a hydroperoxy compound of formula (IV-OOH)

where R₃, R₄, R₅, R₆, R₉, R₁₁, R₁₇, R_(b) and R₇₋₂ are as defined abovewith a hydroperoxy-deoxygenating agent.

Further disclosed is a process for the preparation of a carboxylic acidof formula (VI)

or pharmaceutically acceptable salt thereof, where R₃, R₄, R₅ and R₆ areas defined for the cis and trans enedione (III-cis) and (III-trans) andwhere R₉, R₁₁ and R₁₇ are as defined above; which comprises:

(1) contacting a hydroperoxy compound of formula (IV-OOH)

where R₃, R₄, R₅, R₆, R₉, R₁₁, R₁ R_(b) and R₇₋₂ are as defined above;with a carboxylic acid forming agent selected from the group consistingof:

-   -   (a) heat,    -   (b) a base whose conjugate acid has a pK_(a) of about 5 or        above,    -   (c) an acid which has a pK_(a) of less than about 3,    -   (d) an acylating agent.

Additionally disclosed is a process for the preparation of a carboxylicacid of formula (VI)

where R₃, R₄, R₈ and R₆ are as defined for the cis and trans enedione(III-cis) and (III-trans) and where R₉, R₁₁ and R₁₇ are as definedabove; which comprises:

(1) contacting a hydroxy compound of formula (IV-OH)

or a biscarbonyl compound of formula (V)

or mixture thereof, where R₃, R₄, R₅ and R₆ are as defined for the cisand Trans enedione (III-cis) and (III-trans) and where R₉, R₁₁, R₁₇ andR_(b) are as defined above; with an oxidatively cleaving agent.

Disclosed is a process for the preparation of a 5,7-lactone of formula(VII)

where

-   -   (Va) R₂ is —H:—H; R₃ is ═O; R₄ is —H:—H;    -   (Vb) R₂ is —H:—H; R₃ is R_(3a):R_(3b) where both R_(3a) and        R_(3b) are —OH and R₄ is —H:—H;

where R₉, R₁₁ and R₁₇, are as defined above; which comprises:

(1) contacting a carboxylic acid of formula (VI)

where

-   -   (I) R₃ is ═O; R₄ is R₄₋₁:R₄₋₂ where one of R₄₋₁ and R₄₋₂ is —H        and the other of R₄₋₁ and R₄₋₂ is taken together with R₅ to form        a second bond between the carbon atoms to which they are        attached; R₆ is —H:—H;    -   (III) R₃ is α-R₃₋₅:β-R₃₋₆ where R₃₋₅ is —O—R₃₁ and R₃₋₆ is —R₃₂        where R₃₁ and R₃₂ are the same or different and are selected        from the group consisting of

C₁-C₃ alkyl and

R₃₁ and R₃₂ are taken with the attached O—C—O— to form a Cyclic ketal of5 or 6 atoms of the formula—(CH₂)—CR₃₃R₃₄)_(n1)—(CH₂)—

where n₁ is 0 or 1;

where R₃₃ and R₃₄ are the same or different and are —H and C₁-C₃ alkyl;R₄ is —H:—H; R₆ is R₆₋₅:R₆₋₆ where one of R₆₋₅ and R₆₋₆ is takentogether with R₅ to form a second bond between the carbon atoms to whichthey are attached and the other of R₆₋₅ and R₆₋₆ is —H;

-   -   (IV) R₃ is α-R₃₋₇:β-R₃₋₈ where R₃₋₇ is —O—R₃₁ and R₃₋₉ is O—R₃₂        where R₃₁ and R₃₂ are as defined above; R₄ is R₄₋₇:R₄₋₈ where        one of R₄₋₇ and R₄₋₈ is taken together with R₅ to form a second        bond between the carbon atoms to which they are attached and the        other of R₄₋₇ and R₄₋₈ is —H; R₆ is —H:—H,

where R₉, R₁₁ and R₁₇ are as defined above; with a reaction medium whichhas a pH of less than about 5.

Also disclosed is a process for the preparation of a 5,7-lactone offormula (VII)

where

-   -   (Va) R₂ is —H:—H, R₃ is ═O and R₄ is —H:—H;

where R₉, R₁₁ and R₁₇ are as defined above; which comprises:

(1) contacting a carboxylic acid of formula (VI)

where

(I) R₃ is ═O; R₄ is R₄₋₁:R₄₋₂ where one of —R₁ and R₄₋₂ is —H and theother of R₄₋₁ and R₄₋₂ is taken together with R₅ to form a second bondbetween the carbon atoms to which they are attached; R₆ is —H:—H;

where R₉, R₁₁, and R₁₇ are as defined above; under anhydrous conditionswith an anhydrous reaction medium of pH less than about 5.

Disclosed is a process for the preparation of a 5,7-lactone of formula(VII).

where

-   -   (Vc) R₂ is —H:—H, R₃ is —O—R₃:—O—R_(3b) where R_(3a) and R_(3b)        the same and are C₁-C₃ alkyl or where R_(3a) and R_(3b) are        taken together with the attached O—C—O— to form a cyclic ketal        of 5 or 6 atoms of the formula        —(CH₂)—(CR₃₃R₃₄)_(n1)—(CH₂)—

where n₁ is 0 or 1;

where R₃₃ and R₃₄ are the same or different and are —H and C₁-C₃ alkyl,and R₄ is —H:—H;

(VI) R₂ is —H:—H; R₃ is R_(3c):R_(3d) and R₄ is R_(4c):R_(4d) where oneof R_(3c) and R_(3d) is taken with one of R_(4c) or R_(4d) to form asecond bond between the carbon atoms to which they are attached and theother of R_(3c) and R_(3d) is CH₃—O— or C₂H₅—O—;

and the other of R_(4c) and R_(4d) is —H; or

-   -   (VII) R₂ is R_(2e):R_(2f) and R₃ is R_(3e):R_(3f) where one of        R_(2e) and R_(2f) is taken with one of R_(3e) or R_(3f) to form        a second bond between the carbon atoms to which they are        attached and the other of R_(2e) and R_(2f) is —H, and the other        of R_(3e) and R_(3f) is CH₃—O— or C₂H₅—O—; or mixtures thereof;

where R₉, R₁₁ and R₁₇ are as defined above;

where

-   -   (III) R₃ is α-R₃₋₅:β-R₃₋₆ where R₃₋₅ is —O—R₃₁ and R₃₋₆ is        —O—R₃₂ where R₃₁ and R₃₂ are the same or different and are        selected from the group consisting of

C₁-C₃ alkyl and

R₃₁ and R₃₂ are taken with the attached O—C—O— to form a cyclic ketal of5 or 6 atoms of the formula—(CH₂)—(CR₃₃R₃₄)_(n1)—(CH₂)—

where n₁ is 0 or 1;

where R₃₃ and R₃₄ are the same or different and are —H and —C₁-C₃ alkyl;R₄ is —H:—H; R₆ is R₆₋₅:R₆₋₆ where one of R₆₋₅ and R₆₋₆ is takentogether with R₅ to form a second bond between the carbon atoms to whichthey are attached and the other of R₆₋₅ and R₆₋₆ is —H;

-   -   (IV) R₃ is α-R₃₋₇:β-R₃₋₈ where R₃₋₇ is —O—R₃₁ and R₃₋₈ is —O—R₃₂        where R₃₁ and R₃₂ are as defined above; R₄ is R₄₋₇:R₄₋₈ where        one of R₄₋₇ and R₄₋₈ is taken together with R₅ to form a second        bond between the carbon atoms to which they are attached and the        other of R₄₋₇ and R₄₋₈ is —H; R₆ is —H:—H;

where R₉, R₁₁ and R₁₇ are as defined above; with at least a catalyticamount of acid.

Disclosed is a process for the preparation of a methyl ester of formula(VIII)

where

(I) R₃ is ═O; R₄ is R₄₋₁:R₄₋₂ where one of R₄₋₁ and R₄₋₂ is —H and theother of R₄₋₁ and R₄₋₂ is taken together with R₅ to form a second bondbetween the carbon atoms to which they are attached; R₆ is —H:—H;

where R₉, R₁₁ and R₁₇ are as defined above; which comprises:

(1) contacting a 5,7-lactone of the formula (VII)

where R₄ is —H:—H and where R₃, R₉, R₁₁ and R₁₇ are defined above, withbase, and

(2) contacting the reaction mixture of step (1) with a methylatingagent.

Also disclosed is a process for the preparation of a carboxylic acid ofthe formula (VI)

or pharmaceutically acceptable salts there of, where

(I) R₃ is ═O; R₄ is R₄₋₁:R₄₋₂ where one of R₄₋₁ and R₄₋₂ is —H and theother of R₄₀₋₁ and R₄₋₂ is taken together with R₅ to form a second bondbetween the carbon atoms to which they are attached; R₆ is —H:—H;

where R₉, R₁₁, R₁₇ are as defined above; which comprises:

(1) contacting a 5,7-lactone of formula (VII)

where R₄ is —H:—H; and where R₃, R₉, R₁₁ and R₁₇ are as defined above,with a reaction medium which as a pH>7.

Further disclosed is a process for the preparation of a cis-oxyenedioneof the formula (X-cis)

where R₃, R₄, R₅, and R₆ are as defined for the cis and trans enedione(III-cis) and (III-trans) and where R₉, R₁₁, R₁₇, R_(b), R_(c) and R_(d)are as defined above; which comprises:

(1) contacting a 7α-substituted steroid of formula (II)

where R₃, R₄, R₅, and R₆ are as defined for the cis and trans enedione(III-cis) and (III-trans) and where R₇₋₁, R₉, R₁₁ and R₁₇ are as definedabove; with ozone in the presence of a C₁-C₄ alcohol and

(2) contacting the mixture of step (1) with a hydroperoxy-deoxygenatingagent.

Additionally disclosed is a process 355. A process for the preparationof a trans-oxyenedione of the formula (X-trans)

where R₃, R₄, R₅, and R₆ are as defined for the cis and trans enedione(III-cis) and (III-trans) and where R₉, R₁₁, R₁₇, R_(b), R_(c) and R_(d)are as defined above; which comprises:

(1) contacting a cis-oxyenedione of the formula (X-cis)

where R₃, R₄, R₅, R₆, R₉, R₁₁, R₁₇, R_(b), R_(c) and R_(d) are asdefined above, with an isomerization catalyst selected from thegroup-consisting of:

(a) a strong acid of pK_(a) of <about 2;

(b) a tertiary amine whose conjugate acid has a pK_(a)>about 8 and

(c) salt of a tertiary amine whose conjugate acid has a pK_(a)>about 8,

(d) I₂,

(e) (C₁-C₄)₃P,

(f) φ₃P,

(e) heating to about 80°;

Disclosed is a process for the preparation of a hydroxy compound offormula (IV-OH)

where R₃, R₄, R₅, and R₆ are as defined for the cis and trans enedione(Ill-cis) and (III-trans) and where R₇₋₂, R₉, R₁₁, R₁₇ and R_(b) are asdefined above; or a hydroperoxy compound of formula (IV-OOH)

where R₃, R₄, R₅, R₆, R₇₋₂, R₉, R₁₁, R₁₇ and R_(b) are as defined above,or a biscarbonyl compound of formula (V)

where R₃, R₄, R₅, R₆, R₉, R₁₁, R₁₇ and R_(b) are as defined above, or acarboxylic acid of formula (VI)

where R₃, R₄, R₅, R₆, R₉, R₁, and R₁₇ are as defined above, or a mixturethereof, which comprises:

(1) contacting an oxyenedione of the formula (X-cis)

where R₃, R₄, R₅, R₆, R₉, R₁₁, R₁₇, R_(b), R_(c) and R_(d) are asdefined above or an oxyenedione of the formula (X-trans)

where R₃, R₄, R₅, R₆, R₉, R₁₁, R₁₇, R_(b), R_(c), and R_(d) are asdefined above or mixture there of, with ozone in the presence of analcohol of the formula R₇₋₂—OH where R₇₋₂ is as defined above.

Also disclosed is a process to prepare a carboxylic acid of formula (VI)

or salt thereof where R₃, R₄, R₅, and R₆ are as defined for the cis andtrans enedione (III-cis) and (III-trans) and where R₉, R₁₁ and R₁₇ areas defined above; which comprises:

(1) contacting a 7α-substituted steroid of formula (II)

where R₃, R₄, R₆, and R₆ are as defined for the cis and trans enedione(III-cis) and (III-trans) and where R₇₋₁, R₉, R₁₁ and R₁₇, are asdefined above; with an agent selected from the group consisting of:

-   -   (a) a halogenating agent in the presence of water and a base        whose conjugate acid has a pK_(a) of >about 8,    -   (b) an oxygen donating agent,    -   (c) electrochemical oxidation,    -   (d) a quinone in the presence of water or    -   (e) nonquinone oxidants; and

(2) contacting the reaction mixture of step (1) with ozone in thepresence of an alcohol of the formula R₇₋₂—OH where R₇₋₂ is as definedabove;

(3) contacting the reaction mixture of step (2) with a hydroperoxydeoxygenating agent and

(4) contacting the reaction mixture of step (3) with an oxidativelycleaving agent.

Disclosed is a process to prepare a carboxylic acid of formula (VI)

or salt thereof where R₃, R₄, 8, and R₆ are as defined for the cis andtrans enedione (III-cis) and (III-trans) and where R₉, R₁₁ and R₁₇ areas defined above; which comprises:

(1) contacting a 7α-substituted steroid of formula

where R₃, R₄, R₅, and R₆ are as defined for the cis and trans enedione(III-cis) and till-trans) and where R₇₋₁, R₉, R₁₁, R₁₇ are as definedabove with

(1) ozone in the presence of an alcohol of the formula R₇₂—H where R₇₋₂is as defined above;

(2) contacting the reaction mixture of step (1) with a hydroperoxydeoxygenating agent and

(3) contacting the reaction mixture of step (2) with an oxidativelycleaving agent.

Also disclosed is a process for the preparation of a carboxylic acid offormula (VI)

where R₃, R₄, R₅, and R₆ are as defined for the cis and trans enedione(III-cis) and (III-trans) and where R₉, R₁₁ and R₁₇ are as definedabove, which comprises:

(1) contacting a cis oxyenedione of the formula (X-cis)

or a trans oxyenedione of the formula (X-trans)

or mixture thereof where R₃, R₄, R₅, and R₆ are as defined for the cisand trans enedione (III-cis) and (III-trans) and where R₉, R₁₁, R₁₇,R_(b), R_(c) and R_(d) are as defined above, with an oxidativelycleaving agent.

Also disclosed is a process for the preparation of a Δ⁹⁽¹¹⁾-17-lactone(CII)

which comprises:

(1) contacting a 11α-hydroxy-17-lactone (CI)

with a N-fluoroalkylamine reagent of formula (CVI).

where:

Z₁ is C₁-C₄ alkyl;

Z₂ is C₁-C₄ alkyl and where Z₁ and Z₂ together with the attachednitrogen atom form a 5- or 6-member heterocycle selected from the groupconsisting of pyrrolidinyl, piperazinyl, piperidinyl and morpholinyl;

Z₃ is —F or —CF₃.

Further disclosed is a process for the preparation of a Δ⁹⁽¹¹⁾-steroid(CV)

where W₅ is:

-   -   (1) nothing, there is a double bond between C₄ and C₅;    -   (2) W₆ is W₆₋₁:W₆₋₂ where one of W₆₋₁ or W₆₋₂ is taken together        with W₅ to form a second bond between the carbon atoms to which        they are attached and the other of W₆₋₁ and W₆₋₂ is —H;    -   (3) W₅ is α-O— and W₇ is α-W₇₋₁:β-W₇₋₂ where W₇₋₁ is —CO—        resulting in a lactone (—O—CO—) with the oxygen atom bonded to        the C-5 position in the α-configuration and the carbonyl group        bonded to the C-7 position in the α-configuration, W₇₋₂ is —H;

where W₆ is:

-   -   (1) —H;—H;    -   (2) is W₆₋₃:W₆₋₄ where one of W₆₋₃, and W₆₋₄ is taken together        with W₅ to form a double bond between C-5 and C-6 and the other        of W₆₋₃ and W₆₋₄ is —H;    -   (3) is W₆₋₃:W₆₋₄ and W₇ is W₇₋₃:W₇₋₄ where one of W₆₋₃ and W₆₋₄        is taken together with one of W₇₋₃ or W₇₋₄ to form a double bond        between C-6 and C-7, the other of W₆₋₃ and W₆₋₄ is —H, the other        of W₇₋₃ and W₇₋₄ is —H;

where W₇ is:

-   -   (1) α-W₇₋₅:β-W₇₋₆ where W₇₋₅ is:        -   (a) —H,        -   (b) —C≡N.        -   (c) —C≡C—H,        -   (d) —CH═CH—CH₃,        -   (e) —CO—OH,        -   (f) —CO—OW_(7-5A) where W_(7-5A) is:            -   (i) C₁-C₄ alkyl,            -   (ii) —φ optionally substituted with one thru three C₁-C₃                alkyl, —F, —Cl, —Br, —I, C₁-C₃ alkoxy,        -   (g) —φ optionally substituted with one thru three C₁-C₃            alkyl, —F, —Cl, —Br, —I, C₁-C₃ alkoxy,        -   (h) —CO—SW_(7-5A) where W_(7-5A) is as defined above,        -   (i) —CO—CH═CH—O—CO—W_(7-5A) where W_(7-5A) is as defined            above,        -   (j) —CO—CO—H,        -   (k) —CH₂—NO₂,        -   (l) —S—CO—W_(7-5A) where W_(7-5A) is as defined above,        -   (m) 5-methylfur-2-yl,        -   (n) 5-t-butylfur-2-yl, and W₇₋₆ is —H;    -   (3) α-W₇₋₇:β—W₇₋₈ where W₇₋₇ is —H and W₇₋₈ is:        -   (a) —H,        -   (b) —O—CO—(C₁-C₄ alkyl),        -   (c) —O—CO—OW_(7-8A) where W_(7-8A) is:            -   (i) C₁-C₄ alkyl,            -   (ii) —φ optionally substituted with optionally                substituted with one thru three C₁-C₃ alkyl, —F, —Cl,                —Br, —I, C₁-C₃ alkoxy.            -   (iii) —CH₂—φ where —φ is optionally substituted with one                thru three C₁-C₃ alkyl, —F, —Cl, —Br, —I, C₁-C₃ alkoxy;                which comprises:

(1) contacting a 11α-hydroxy steroid (CIV)

where W₅, W₆ and W₇ are as defined above, with a N-fluoroalkylaminereagent of the formula (CVI)

where:

Z₁ is C₁-C₄ alkyl;

Z₂ is C₁-C₄ alkyl and where Z₁ and Z₂ together with the attachednitrogen atom form a 5- or 6-member heterocycle selected from the groupconsisting of pyrrolidinyl, piperazinyl, piperidinyl and morpholinyl;

Z₃ is —F or —CF₃.

Additionally disclosed is a process for the preparation of aΔ⁹⁽¹¹⁾-7α-substituted steroid of the formula (II)

where R₁₇ is

-   -   (1) ═O;    -   (3) α-R₁₇₋₃:β-R₁₇₋₄ where R₁₇₋₃ is —H and where R₁₇₋₄ is:        -   (a) —CO—CH₃,        -   (b) —CO—CH₂—OH,        -   (c) —CO—CH₂—O—CO—(CH₂)₀₋₃—CH₃;    -   (4) α-R₁₇₋₅:β-R₁₇₋₄ where R₁₇₋₅ and R₁₇₋₆ are taken with the        attached carbon atom to form a three member epoxide containing        —O—CH₂— where the attachment of the —O is at R₁₇₋₆ in the        β-orientation and the attachment of the CH₂— is at R₁₇₋₅ in the        α-orientation;    -   (5) α-R₁₇₋₅:β-R₁₇₋₆ where R₁₇₋₅ and R₁₇₋₈ are taken with the        attached carbon atom to form a five member lactone containing        —O—CH₂—CH₂— where the attachment of the CH₂— is at R₁₇₋₇ in the        α-orientation and the attachment of the —O is at R₁₇₋₈ in the        β-orientation;    -   (6) —O—CH(OR₁₇₋₉)—CH₂—CH₂ . . . where the bond from the oxygen        (—O) is one of the four bonds at C-17 in the β-configuration and        the bond from the methylene group (CH₂ . . . ) is another of the        four bonds at C-17 in the α-configuration to form a 5 member        heterocycle containing one oxygen atom, where R₁₇₋₉ is —H or        C₁-C₃ alkyl;    -   (7) α-R₁₇₋₁₁:β-R₁₇₋₁₂ where R₁₇₋₁₀ is —(CH₂)₁₋₂—CH═CH₂ and        R₁₇₋₁₂ is —OH;

where R₃, R₄, R₅, and R₆ are as defined for the cis and trans enedione(III-cis) and (III-trans) and where R₇₋₁ is as defined above, whichcomprises contacting a 11α-hydroxy 7α-substituted steroid of the formula(II)

where R₃, R₄, R₅, R₆ R₇₋₁ and R₁₇ are as defined above, with aN-fluoroalkylamine reagent of formula (CVI).

Disclosed is a process for the preparation of a Δ⁹⁽¹¹⁾-trans enedione ofthe formula (III-trans)

where R₁₇ is:

-   -   (1) ═O;    -   (3) α-R₁₇₋₃:β-R₁₇₋₄ where R₁₇₋₃ is —H and where R₁₇₋₄ is:        -   (a) —CO—CH₃,        -   (b) —CO—CH₂—OH,        -   (c) —CO—CH₂—O—CO—(CH₂)₀₋₃—CH₃;    -   (4) α-R₁₇₋₅:βR₁₇₋₆ where R₁₇₋₅ and R₁₇₋₆ are taken with the        attached carbon atom to form a three member epoxide containing        —O—CH₂— where the attachment of the —O is at R₁₇₋₆ in the        β-orientation and the attachment of the CH₂— is at R₁₇₋₅ in the        α-orientation;    -   (5) α-R₁₇₋₇:β-R₁₇₋₆ where R₁₇₋₇ and R₁₇₋₆ are taken with the        attached carbon atom to form a five member lactone containing        —O—CO—CH₂—CH₂— where the attachment of the CH₂— is at R₁₇₋₇ in        the α-orientation and the attachment of the —O is at R₁₇₋₈ in        the β-orientation;    -   (6) O—CH(OR₁₇₋₉)—CH₂CH₂ . . . where the bond from the oxygen        (—O) is one of the four bonds at 0-17 in the β-configuration and        the bond from the methylene group (CH₂ . . . ) is another of the        four bonds at C-17 in the α-configuration to form a 5 member        heterocycle containing one oxygen atom, where R₁₇₋₉ is —H or        C₁-C₃ alkyl;    -   (7) α-R₁₇₋₁₁:βR₁₇₋₁₂ where R₁₇₋₁₀ is —(CH₂)₁₋₂—CH═CH₂ and R₁₇₋₁₂        is —OH;

where R₃, R₄, R₅, and R₆ are as defined for the cis and trans enedione(III-cis) and (III-trans) and where R_(b), R_(c) and R_(d) are asdefined above, which comprises contacting a 11α-hydroxy cis enedione ofthe formula (III-cis)

or a 11α-hydroxy trans enedione of the formula (III-trans)

where R₃, R₄, R₅, R₆, R₁₇, R_(b), R_(c) and R_(d) are as defined above,with a N-fluoroalkylamine reagent of formula (CVI).

Also disclosed is a process to prepare a Δ⁹⁽¹¹⁾-carboxylic acid of theformula (VI)

or salt thereof where R₁₇ is:

-   -   (1) ═O;    -   (3) α-R₁₇₋₃:β-R₁₇₋₄ where R₁₇₋₃ is —OH and where R₁₇₋₄ is:        -   (a) —CO—CH₃,        -   (b) —CO—CH₂—OH,        -   (c) —CO—CH₂O—CO—(CH₂)₀₋₃—CH₃;    -   (4) α-R₁₇₋₅:β-R₁₇₋₄ where R₁₇₋₄ and R₁₇₋₈ are taken with the        attached carbon atom to form a three member epoxide containing        O—CH₂— where the attachment of the —O is at R₁₇₋₆ in the        β-orientation and the attachment of the CH₂— is at R₁₇— in the        α-orientation;    -   (5) α-R₁₇₋₇:β-R₁₇₋₈ where R₁₇₋₇ and R₁₇₋₈ are taken with the        attached carbon atom to form a five member lactone containing        —O—CO—CH₂—CH₂— where the attachment of the CH₂— is at R₁₇₋₇ in        the α-orientation and the attachment of the —O is at R₁₇₋₈ in        the β-orientation;    -   (6) —O—CH(OR₁₇₋₉)—CH₂—CH₂ . . . where the bond from the oxygen        (—O) is one of the four bonds at C-17 in the β-configuration and        the bond from the methylene group (CH₂ . . . ) is another of the        four bonds at C-17 in the α-configuration to form a 5 member        heterocycle containing one oxygen atom, where R₁₇₋₉ is —H or        C₁-C₃ alkyl;    -   (7) α-R₁₇₋₁₁:β-R₁₇₋₁₂ where R₁₇₋₁₀ is —(CH₂)₁₋₂—CH═CH₂ and        R₁₇₋₁₂ is —OH;

where R₃, R₄, R₅, and R₆ are as defined for the cis and trans enedione(III-cis) and (III-trans), which comprises

(1) contacting a 11α-hydroxy-hydroxy compound of the formula (IV-OH)

or a 11α-hydroxy-hydroperoxy compound of the formula (IV-OOH)

or a 11α-hydroxy biscarbonyl compound of the formula (V)

where R₃, R₄, R₅, and R₆ are as defined for the cis and trans enedione(III-cis) and (III-trans) and where R₇₋₂, R₁₇ and R_(b), are as definedabove, with a N-fluoroalkylamine reagent of formula (CVI) and

(2) contacting the reaction mixture of step (1) with an oxidativelycleaving agent.

DETAILED DESCRIPTION OF THE INVENTION

Eplerenone is9α,11α-epoxy-17β-hydroxypregn-4-en-3-one-7α,21-dicarboxylic acid,γ-lactone, methyl ester and as such contains a 7α-carbomethoxysubstituent. It is useful as a pharmaceutical agent for the treatment ofhypertension and congestive heart failure. A major difficulty in theproduction of eplerenone is introduction of the 7α-carbomethoxysubstituent. The processes and intermediates of the present inventionare improved processes for the preparation of eplerenone.

CHART A discloses the general process of the invention when the adductat the 7α-position, —R₇₋₁ is (-A1). The process of the present inventionbegins with a protected or unprotected Δ⁴⁻⁶-3-keto steroid (I). Sincethe steroid A-ring can be protected or not protected, CHART B disclosesan improved process for protection of the Δ⁴⁶-3-keto steroid (I)starting material as a C-3 protected Δ^(4,6)-3-ketal steroid (I-P).CHART C discloses an alternative route (ozonolysis) for transformationof the 7α-substituted steroid (II) to eplerenone (IX). CHART D disclosesthe general process when the steroid A-ring is unprotected and R₇₋₁ isthe variable substituent (-A1). CHART E discloses the preferred processfor the transformation of a Δ^(4,6)-3-keto steroid or ketal thereof (I)to eplerenone (IX). CHART F discloses the reversible nature of theconversion of the carboxylic acid (VI) with the 5,7-lactone (VII). CHARTG discloses the general process of the invention when —R₇₋₁ is (-A2).CHART H discloses the general process of the invention when —R₇₋₁ is(-B), (-C), (-D1), (-D2) or (-D3).

The first step in the process of CHART A is to prepare a 7α-substitutedsteroid (II) of the formula

where

(I) R₃ is ═O; R₄ is R₄—:R₄₋₂ where one of R₄₋₁ and R₄₋₂ is —H and theother of R₄₋₁ and R₄₋₂ is taken together with R₅ to form a second bondbetween the carbon atoms to which they are attached; R₆ is —H:—H;

(II) R₃ is R₃₋₃:R₃₋₄ and R₄ is R₄₋₃:R₄₋₄ where one of R₃₋₃ and R₃₋₄ is—O—R₃₁ where R₃₁ is C₁-C₃ alkyl, the other of R₃₋₃ and R₃₋₄ is takentogether with one of R₄₋₃ and R₄₋₄ to form a second bond between thecarbon atoms to which they are attached, and the other of R₄₋₃ and R₄₋₄is —H; R₆ is R₆₋₃:R₆₋₄ where one of R₆₋₄ and R₆₋₄ is taken together withR₅ to form a second bond between the carbon atoms to which they areattached and the other of R₆₋₃ and R₆₋₄ is —H;

(III) R₃ is α-R₃₋₅:β-R₃₋₆ where R₃₋₅ is —O—R₃, and R₃₋₆ is O—R₃₂ whereR₃₁ and R₃₂ are the same or different and are selected from the groupconsisting of

-   -   C₁-C₃ alkyl and    -   R₃₁ and R₃₂ are taken with the attached —O—C—O— to form a cyclic        ketal of 5 or 6 atoms of the formula        —(CH₂)—(CR₃₃R₃₄)_(n1)—(CH₂)—

where n₁ is 0 or 1;

where R₃₃ and R₃₄ are the same or different and are —H and C₁-C₃ alkyl;R₄ is —H:—H; R₆ is R₆₋₅:R₆₋₆ where one of R₆₋₅ and R₆₋₆ is takentogether with R₅ to form a second bond between the carbon atoms to whichthey are attached and the other of R₆₋₅ and R₆₋₆ is H;

(IV) R₃ is α-R₃₋₇:β-R₃₋₈ where R₃₋₇ is —R₃₁ and R₃₋₈ is —O—R₃₂ where R₃₁and R₃₂ are as defined above; R₄ is R₄₋₇:R₄₋₈ where one of R₄₋₇ and R₄₋₈is taken together with R₅ to form a second bond between the carbon atomsto which they are attached and the other of R₄₋₇ and R₄₋₈ is —H; R₆ is—H:—H;

where R₇₋₁ is a molecular fragment of the formula (-A1)

or of the formula (-A2)

-   -   where X₁ is:        -   —S—,        -   —O— or        -   —NX₁₋₁— and where X₁₋₁ is:            -   —H,            -   C₁-C₄ alkyl,            -   —CO—OX₁₋₂ where X₁₋₂ is C₁-C₄ alkyl or —CH₂—φ,            -   —CO—X₁₋₂ where X₁₋₂ is as defined above,            -   —CO—φ where —φ is substituted in the o-position with                —CO—O—(C₁-C₄ alkyl),            -   —SO, —C₁-C₃ alkyl),            -   —SO₂—φ where φ is optionally substituted with 1 or 2                -   C₁-C₄ alkyl,                -   C₁-C₄ alkoxy;    -   where R_(b) is selected from the group consisting of        -   —H,        -   C₁-C₄ alkyl or        -   phenyl optionally substituted with 1 or 2            -   C₁-C₄ alkyl,            -   C₁-C₄ alkoxy,    -   where R_(c) is selected from the group consisting of:        -   —H,        -   C₁-C₄ alkyl,        -   C₁-C₄ alkoxy,        -   —O—Si(R)₃ where the R's are the same or different and are            —H, C₁-C₄ alkyl, —φ, C₁-C₄ alkoxy and —H,        -   —F, —Cl, —Br, —I,        -   —CO—OCH₃ and        -   —CO—R_(c-1) where R_(c-1) is C₁-C₄ alkyl or —φ;    -   where R_(d) is selected from the group consisting of        -   —H,        -   —C≡N,        -   C₁-C₁₀ alkyl:        -   C₁-C₄ alkoxy;        -   —CH₂—OR_(d-1) where R_(d-1) is —H or C₁-C₄ alkyl,        -   —CH₂—N(R_(d-6))₂ where the two R_(d-6) are the same or            different and are:            -   C₁-C₄ alkyl,            -   —φ,            -   —CO—R_(d-6a) where R_(d-6a) is C₁-C₄ alkyl or —φ,        -   —CH₂—O—CO—R_(d-1) where R_(d-1) is as defined above,        -   —CH(OR_(d-1))₂ where R_(d-1) is as defined above and where            the two R_(d-1) taken together are:            -   —CH₂—CH₂—,            -   —CH₂—CH₂—CH₂—,            -   —CH₂—C(CH₃—)₂—CH₂—,        -   —CH(—O—CO—R_(d-1))₂ where R_(d-1) is as defined above,        -   —Si(R)₃ where R is as defined above,        -   —O—Si(R)₃ where R is as defined above,        -   —Sn(R_(b-1))₃ where R_(b-1) is as defined above,        -   —S—R_(d-5) where R_(d-5) is C₁-C₄ alkyl or —φ.        -   —N(R_(d-6))₂ where R_(d-6) is as defined above,

where R_(c) and R_(d) taken together with the atoms to which they areattached to form

where E₁ are the same or different and are:

-   -   —H,    -   C₁-C₄ alkyl,    -   —F, —Cl, —Br, —I,    -   —OE₁₋₁ where E₁₋₁ is:        -   —H,        -   C₁-C₄ alkyl,        -   —φ or        -   —SiE₁₋₂E₁₋₃E₁₋₄ where E₁₋₂, E₁₋₃ and E₁₋₄ are the same or            different and are C₁-C₄ alkyl or C₁-C₄ alkoxy,    -   —S-E₁₋₅ where E₁₋₅ is C₁-C₄ alkyl or —φ,    -   —S—(O)₁₋₂-E₁₋₅ where E₁₋₅ is as defined above,    -   —N(R_(d-6))₂ where the two R_(d-6) are the same or different and        are as defined above,    -   —P(O)(O-E₁₋₁)₂ where E₁₋₁ is as defined above,    -   —Si(R)₃ where R is as defined above;        —CE₁=M  (-B)

where E₁ is as defined above and

where M is:

-   -   (1) ═O,    -   (2) ═N-E₂ where E₂ is selected from the group consisting of        -   —H        -   C₁-C₄ alkyl,        -   C₁-C₄ alkenyl containing 1 or 2 double bonds,        -   C₁-C₄ alkynyl containing 1 triple bond,        -   —CO—OE₂₋₁ where E₂₋₁ is —H or C₁-C₄ alkyl,        -   —C(E₂₋₁)₂-OE₂₋₂ where E₂₋₁ are the same or different and are            as defined above and where E₂₋₂ is            -   C₁-C₄ alkyl,            -   —φ or            -   —Si(R)₃ where the three R are the same or different and                are defined above,        -   —OE₂₋₂ where E₂₋₂ is as defined above,        -   —S-E₂₋₃ where E₂₋₃ is C₁-C₄ alkyl or —φ.        -   —S—(O)₁₋₂-E₂₋₃ where E₂₋₃ is as defined above,        -   —N(R_(d-6))₂ where the two R_(d6) are the same or different            and are as defined above;        -   —Si(R)₃ where the three R are as defined above;    -   (3) —C(E₂)₂ where the E₂ are the same or different and are as        defined above,

where E₁ and E₂ are taken together with the atoms to which they areattached to form a ring of 5 thru 7 members, optionally containing 3thru 5

-   -   —O—,    -   —S—,    -   —N═,    -   —NX₁₋₁— where X₁₋₁ is as defined above,    -   —CE₂=where E₂ is as defined above,    -   —C(R_(b))₂— where R_(b) is as defined above, and optionally        containing 1 or 2 additional double bonds;        —C≡C-E₂  (—C)

where E₂ is as defined above;—CH₂—CH—CH₂ (-D1)—CH═C═CH₂  (-D2)—CH₂—C≡C—H  (-D3)

where R₉ is:

-   -   (1) —H,    -   (2) —OH,    -   (3) —O-(HYDROXY PROTECTING GROUP) where HYDROXY PROTECTING GROUP        is selected from the group consisting of        -   —Si(—CH₃)₃,        -   —Si(—CH₂—CH₃)₃,        -   —CO—CH₃,        -   —CO—H and        -   —SiH(CH₃)₂,    -   (4) —F;

where R₁₁ is:

-   -   (1) ═O,    -   (2) —H:—H,    -   (3) α-R₁₁₋₁:β-R₁₁₋₂ where R₁₁₋₁ is:        -   (a) —H,        -   (b) —O—R₁₁₋₃ where R₁₁₋₃ is:            -   (i) —H,            -   (ii) a HYDROXY PROTECTING GROUP) where HYDROXY                PROTECTING GROUP is as defined above, and where R₁₁₋₂                is:        -   (a) —H,        -   (b) —O—R₁₁₋₄ where R₁₁₋₄ is:            -   (i) —H,            -   (ii) a HYDROXY PROTECTING GROUP) where HYDROXY                PROTECTING GROUP is as defined above, with the proviso                that one of R₁₁₋₁ and R₁₁₋₂ must be —H,    -   (4) R₁₁₋₅R₁₁₋₆ where one of R₁₁₋₅ or R₁₁₋₆ and R₉ are taken        together with R₉ to form a second bond between C-9 and C-11 and        the other of R₁₁₋₅ or R₁₁₋₆ is —H,    -   (5) α-R₁₁₋₇:β-R₁₁₋₇ where R₁₁₋₇ and R₉ are taken together with        —O— to form an epoxide between C-9 and C-11 and R₁₁₋₈ is —H;

where R₁₇ is:

-   -   (1) ═O;    -   (2) α-R₁₇₋₁:β-R₁₇₋₂ where R₁₇₋₁ is:        -   (a) —H,        -   (b) —C≡C—H,        -   (c) —C≡N,        -   (d) —C≡C—CH₂—O—R₁₇₋₁₋₁ where R₁₇₋₁₋₁ is selected from the            group consisting of            -   (i) —H,            -   (ii) —Si(R₁₇₋₁₋₂)₃ where R₁₇₋₁₋₂ are the same or                different and are C₁-C₄ alkyl,            -   (iii) 1-ethoxyethyl,            -   (iv) 2-tetrahydropyranyl,        -   (e) —C≡C—CH₂—O-(HYDROXY PROTECTING GROUP), where HYDROXY            PROTECTING GROUP is as defined above,        -   (f) —CH₂—CH₂—CH₂—OH,        -   (g) —CH₂—CH₂—CH₂—O-(HYDROXY PROTECTING GROUP) where HYDROXY            PROTECTING GROUP is as defined above,        -   (h) —CH₂—CH₂—CO—O⁻ and where R₁₇₋₂ is —H;    -   (3) α-R₁₇₋₃:β-R₁₇₋₄ where R₁₇₋₃ is —OH and where R₁₇₋₄ is:        -   (a) —CO—CH₃,        -   (b) —CO—CH₂—OH,        -   (c) —CO—CH₂—O—CO—(CH₂)₀₋₃—CH₃;    -   (4) α-R₁₇₋₅:β-R₁₇₋₆ where R₁₇₋₅ and R₁₇₋₆ are taken with the        attached carbon atom to form a three member epoxide containing        —O—CH₂— where the attachment of the —O is at R₁₇₋₆ in the        β-orientation and the attachment of the CH₂— is at R₁₇₋₅ in the        α-orientation;    -   (5) α-R₁₇₋₇:β-R₁₇₋₈ where R₁₇₋₇ and R₁₇₋₈ are taken with the        attached carbon atom to form a five member lactone containing        O—CO—OH₂—CH₂— where the attachment of the CH₂— is at R₁₇₋₇ in        the α-orientation and the attachment of the —O is at R₁₇₋₈ in        the β-orientation;    -   (6) O—CH(OR₁₇₋₉)—CH₂—CH₂ . . . where the bond from the oxygen        (—O) is one of the four bonds at C-17 in the β-configuration and        the bond from the methylene group (CH₂ . . . ) is another of the        four bonds at C-17 in the α-configuration to form a 5 member        heterocycle containing one oxygen atom, where R₁₇₋₉ is —H or        C₁-C₃ alkyl;    -   (7) α-R₁₇₋₁₁:β-R₁₇₋₁₂ where R₁₇₋₁₀ is —(CH₂)₁₋₂—CH═CH₂ and        R₁₇₋₁₂ is —H; which comprises:

(1) contacting a Δ^(4,6)-3-keto steroid or ketal thereof (I) of theformula

where

(I) R₃ is ═O; R₄ is, R₄₋₁:R₄₋₂ where one of R₄₋₁ and R₄₋₂ is —H and theother of R₄₋₁ and R₄₋₂ is taken together with R₅ to form a second bondbetween the carbon atoms to which they are attached;

(I-ketal) R₃ is R₃₋₉:R₃₋₁₀ where R₃₋₉ is —O—R₃₁ and —R₃₋₁₀ is —O—R₃₂where R₃₁ and R₃₂ are the same or different and are selected from thegroup consisting of

-   -   C₁-C₃ alkyl and    -   R₃₁ and R₃₂ are taken with the attached —O—C—O— to form a cyclic        ketal of 5 or 6 atoms of the formula        —(CH₂)—(CR₃₃R₃₄)_(n1)—(CH₂)—

where n₁ is 0 or 1;

where R₃₃ and R₃₄ are the same or different and are —H and C₁-C₃ alkyl;R₄ is R₄₋₉:R₄₋₁₀ where one of R₄₋₉ and R₄₋₁₀ is taken together with R₅to form a second bond between the carbon atoms to which they areattached and the other of R₄₋₉ and R₄₋₁₀ is —H;

where R₉, R₁₁ and R₁₇ are as defined above, with an adduct selected fromcompounds

(a) of the formula (A)

where X₁, R_(b), R_(c) and R_(d) are as defined above, and

where R_(a) is selected from the group consisting of —H, -ZnL, —BL,—SiL₃, —SnL₃, —Cu, —CuL, —AlL₂, —HgL, —Ag, —MgL, —Li and —COOH, where Lis —H, C₁-C₄ alkyl, —F, —Cl, —Br, —I, —CN, —O(C₁-C₃ alkyl), 2-thienyl,(CH₃)₂C(O—)—O(O—)O(CH₃)₂ and

(b) of the formula (A′)R_(b)—CO—CHR_(b)—CHR_(c)—CO—R_(d)  (A′)where R_(b), R_(c) and R_(d) are as defined above;

(c) of the formula (A″)

where R_(e) is:

-   -   C₁-C₄ alkyl,    -   —CO—(C₁-C₄ alkyl or —φ),    -   —Si(R)₃ where R is as defined above and where X₁, R_(b), R_(c)        and R_(d) are as defined above;

(d) of the formula (B)R_(a)—CE₁=M  (B)

-   -   where R_(a), E₁ and M are as defined above;

(e) of the formula (C)R_(a)—C≡C-E₂  (C)

-   -   where R_(a) and E₂ are as defined above;

(f) of the formulas (D1, D2 and D3)R_(a)—CH₂—CH═CH₂  (D1)R_(a)—CH═C═CH₂  (D2)R_(a)—CH₂—C≡C—H  (D3)where R_(a) is as defined above, in the presence of:

(1) a Lewis Acid,

(2) a proton acid with a pK_(a) of <about 5 or

(3) a salt of a secondary amine of the formula

where

-   -   R_(S-2) is —H, C₁-C₄ alkyl, —φ, and —CH₂—φ;    -   R_(S-3) is —H, C₁-C₄ alkyl;    -   R_(S-4) is —H, C₁-C₄ alkyl, —φ;    -   R_(S-5) is —H, C₁-C₄ alkyl —φ;        and

where

-   -   R_(S-2) is —H, C₁-C₄ alkyl, —φ, and —CH₂—φ;    -   R_(S-4) is —H, C₁-C₄ alkyl, —φ;    -   R_(S-5) is —H, C₁-C₄ alkyl, —φ;        with an acid of pK_(a) of <about 2.

For the Δ⁴-3-keto or ketal thereof (I) starting material it is preferredthat R₃, R₄ and R₅ are (I) R₃ is ═O; R₄ is R₄₋₁:R₄₋₂ where one of R₄₋₁and R₄₋₂ is —H and the other of R₄₋₁ and R₄₋₂ is taken together with R₅to form a second bond between the carbon atoms to which they areattached; R₆ is —H:—H.

For the 7α-substituted steroid (II), there were four sets of steroidA-/B-rings identified above. Groups (I), (III) and (IV) are operable inthe processes of the present invention. However, group (II) where R₃ isR₃₋₃:R₃₋₄ and R₄ is R₄₋₃:R₄₋₄ where one of R₃₋₃ and R₃₋₄ is —O—R₃₁ whereR₃₁ is C₁-C₃ alkyl, the other of R₃₋₃ and R₃₋₄ is taken together withone of R₄₋₃ and R₄₋₄ to form a second bond between the carbon-atoms towhich they are attached, and the other of R₄₋₃ and R₄₋₄ is —H; R₆ isR₆₋₃:R₆₋₄ where one of R₆₋₃ and R₆₋₄ is taken together with R₅ to form asecond bond between the carbon atoms to which they are attached and theother of R₆₋₃ and R₆₋₄ is —H; is a Δ^(3,6)-3,3-dialkoxy ring systemwhich, as such, can not be transformed to the other intermediates of thepresent invention. It is useful because it can be transformed to thecorresponding Δ⁴-3-keto steroid A-/B-ring system which is useful in theprocesses of the present invention.

For the 7α-substituted steroid (II) and other steroidal compounds of theinvention, except the 5,7-bislactone (VII), with regard to the steroidalA-/B-rings, it is preferred that R₃, R₄, R₅ and R₆ are selected from thegroup consisting of:

(I) R₃ is ═O; R₄ is R₄₋₁:R₄₋₂ where one of R₄₋₁ and R₄₋₂ is —H and theother of R₄₋₁ and R₄₋₂ is taken together with R₅ to form a second bondbetween the carbon atoms to which they are attached; R₆ is —H:—H;

(III) R₃ is α-R₃₋₅:β-R₃₋₆ where R₃₋₅ is —O—R₃₁ and R₃₋₆ is —O—R₃₂ whereR₃₁ and R₃₂ are taken with the attached —O—C—O— to form a cyclic ketalof 5 atoms of the formula —(CH₂)—(CR₃₃R₃₄)_(n1)—(CH₂)— where n₁ is 0; R₄is —H:—H; R₆ is R₆₋₅:R₆₋₆ where one of R₆₋₅ and R₆₋₆ is taken togetherwith R₅ to form a second bond between the carbon atoms to which they areattached and the other of R₆₋₅ and R₆₋₆ is —H;

(III) R₃ is α-R₃₋₅:β-R₃₋₆ where R₃₋₅ is —O—R₃₁ and R₃₋₆ is —O—R₃₂ whereR₃₁ and R₃₂ are taken with the attached —O—C—O— to form a cyclic ketalof 6 atoms of the formula —(CH₂)—(CR₃₃R₃₄)_(n1)—(CH₂)— where n₁ is 1 andR₃₃ and R₃₄ are both C₁ alkyl; R₄ is —H:—H; R₆ is R₆₋₅:R₆₋₆ where one ofR₆₋₅ and R₆₋₆ is taken together with R₅ to form a second bond betweenthe carbon atoms to which they are attached and the other of R₆₋₅ andR₆₋₆ is —H.

For the 7α-substituted steroid (II) and other steroidal compounds of theinvention, except the 5,7-bislactone (VII), with regard to the steroidalA-/B-rings, it is more preferred that R₃, R₄, R₅ and R₆ are:

(I) R₃ is ═O; R₄ is R₄₋₁:R₄₋₂ where one of R₄₋₁ and R₄₋₂ is —H and theother of R₄₋₁ and R₄₋₂ is taken together with R₅ to form a second bondbetween the carbon atoms to which they are attached; R₆ is —H:—H.

With regard to the steroidal C-ring, it is preferred that R₉ and R₁₁are:

-   -   (a) R₁₁ is R₁₁₋₅:R₁₁₋₆ where one of R₁₁₋₅ or R₁₁₋₆ and R₉ are        taken together with R₉ to form a second bond between C-9 and        C-11 and the other of R₁₁₋₅ or R₁₁₋₆ is —H,    -   (b) α-R₁₁₋₇:β-R₁₁₋₈ where R₁₁₋₇ and R₉ are taken together with        —O— to form an epoxide between C-9 and C-11 and R₁₁₋₈ is —H,    -   (c) R₉ is —H and R₁₁ is α-R₁₁₋₁:β-R₁₁₋₂ where R₁₁₋₁ is —O—R₁₁₋₃        where R₁₁₋₃ is —H, and where R₁₁₋₂ is —H. It is more preferred        that R₉ and R₁₁ are:    -   (a) R₁₁ is R₁₁₋₅:R₁₁₋₆ where one of R₁₁₋₅ or R₁₄ and R₉ are        taken together with R₉ to form a second bond between C-9 and        C-11 and other of R₁₁₋₅ or R₁₁₋₄ is —H.

With regard to the steroidal D-ring, it is preferred that R₁₇ isselected from the group consisting of:

-   -   (a) α-R₁₇₋₇:β-R₁₇₋₈ where R₁₇₋₇ and R₁₇₋₈ are taken with the        attached carbon atom to form a five member lactone containing        —CO—CH₂—CH₂— where the attachment of the CH₂— is at R₁₇₋₇ in the        α-orientation and the attachment of the —O is at R₁₇₋₈ in the        β-orientation,    -   (b) ═O;    -   (c) α-R₁₇₋₁:β-R₁₇₋₂ where R₁₇₋₁ is —C≡C—H and where R₇₋₂ is —OH,    -   (d) —C≡C—CH₂—O—R₁₇₋₁₋₁.

With regard to the 7α-substituted steroid (II), it is preferred thatR₇₋₁ is substituent of formula (-A1). It is also preferred that X₁ is—O—. It is preferred that R_(b) and R_(c) are —H and it is preferredthat R_(d) is C₁ alkyl. It is preferred that R_(a) is —H. It ispreferred that for R_(a) that L is

-ZnL is —Cl, —Br, —I;

—BL is catecholate,

-   -   two —OH,    -   HO—CH₂—CH₂—OH,    -   HO—CH₂—CH₂—CH₂—OH,    -   HO—CH₂—C(CH₃)₂—CH₂—OH;

—SiL₃ is C₁ alkyl;

—SnL₃ is C₁ or n-C₄ alkyl;

—CuL is 2-thienyl or —CN and

—AlL₂ is C₁-C₂ alkyl.

When R_(a) is Cu, there can be two R_(a) groups for one Cu in which casethe Cu is anionic.

The preferences lot the variable substituents R₃, R₄, R₅, R₆, R₇₋₁, R₉,R₁₁, R₁₇, R_(a), R_(b), R_(c), R_(d) and X₁ are not just for theΔ^(4,6)-3-keto steroid or ketal thereof (I) and/or the 7α-substitutedsteroid (II), but rather are for all the compounds (I) thru (XV) of theinvention, except as expressly noted. Similarly, the preferences forother variable substituents such as R₇₋₂ discussed below and/or chemicalreagents used in this patent such as oxygen donating agent, halogenatingagent, isomerization catalyst, hydroperoxy-deoxygenating agent, acidforming agent, acylation catalyst, oxidatively cleaving agent,deoxygenating agent, are defined the same throughout the patent as thefirst time they are discussed. Since many of these variable substituentsand chemical reagents are referred to numerous times, it would beredundant each time they are used to repeatedly mention what isincluded, what is preferred and more preferred.

It is preferred that the acid reactant be a Lewis acid. The Lewis acidmust-e electrophilic enough to complex with the Δ^(4,6)-3-keto steroidor ketal thereof (I), but not so electrophilic that it complexes withthe nucleophilic reagent (A1), (A2), (B), (C), (D1), (D2) or (D3) as isknown to those skilled in the art. Further, it is preferred that theLewis Acid be used in the presence of an alcohol selected from the groupconsisting of C₁-C₃ alcohols, ethylene glycol, 1,2- or 1,3-propyleneglycol, 2,2-dimethyl- or 2,2-diethyl-1,3-propylene glycol and phenol. Itis more preferred that the alcohol be a C₁-C₃ alcohol or mixturethereof. Useful Lewis acids include those selected from the groupconsisting of

BX₃, AlX₃, SnX₂, SnX₄, SiX₄, MgX₂, ZnX₂, TiX₄,

Rh(acac)(CH₂CH₂)₂(2,2′-bis(diphenylphosphino)-1,1′-binaphthyl),

Rh(CH₃—C≡N)₂(cyclooctadiene)(BF₄),

Rh(acac)(CH₂CH₂)₂(dppb),

LiClO₄,

K10 Montmorillonite clay,

Yb(OTf)₃,

LiCo(B₉C₂H₁₁)₂,

PdX₂,

CrX₃,

FeX₃,

CoX₃,

NiX₂,

SbX₅,

InX₃,

Sc(OTf)₃,

φ₃C⁺X⁻

(R)₃SiX where R is C₁-C₄ alkyl and —φ; where X is selected from thegroup consisting of F⁻, Cl⁻, Br⁻, I⁻, —O—SO₂CF₃ ⁻, PF₆ ⁻, BF₄ ⁻, andClO₄ ⁻;

Pd(CH₃—CO—O⁻)₂;

BF₃-diethyletherate complex;

BF₃-acetic acid complex;

BF₃-methyl-t-butyl ether complex;

BF₃-di-n-butyletherate complex;

BF₃-dimethyletherate complex;

BF₃-dimethylsulfide complex;

BF₃-phenol complex;

BF₃-phosphoric acid complex and

BF₃-tetrahydrofuran complex. It is preferred that the Lewis acid isselected from the group consisting of BF₃, BF₃-diethyletherate complex,BF₃-acetic acid complex, BF₃-methyl-t-butyl ether complex,BF₃-di-n-butyletherate complex, BF₃-dimethyletherate complex,BF₃-dimethylsulfide complex, BF₃-phenol complex, BF₃-phosphoric acidcomplex and BF₃-tetrahydrofuran complex. It is more preferred that theLewis acid is BF₃-diethyletherate. It is even more preferred that theBF₃-diethyletherate is used in the presence of C₁-C₃ alcohol and stillmore preferred is the use of the BF₃-diethyletherate in the presence ofC₂ alcohol. Useful acids with a pK_(a) of <about 5 are selected from thegroup consisting of formic acid, acetic acid, propionic acid, benzoicacid, acid, hydrofluoric acid, fluoroboric acid, p-toluenesulfonic acid,methanesulfonic acid, benzenesulfonic acid, trifluoromethanesulfonicacid, perchloric acid, trifluoroacetic and trichloroacetic. It ispreferred that the acid with a pK_(a) of <about 5 is acetic acid. Whenperforming the transformation of the Δ^(4,6)-3-keto steroid or ketalthereof (I) to the corresponding 7α-substituted steroid (II), at leastone equivalent of the reagent of formulas (A), (B) or (C) should beused, it is preferable to use from one to two equivalents. Use ofadditional reagent is not a problem, but rather a waste of compound. Thereaction can be carried out in a variety of solvents, such as in asolvent/solvent mixture selected from the group consisting of:

C₁-C₆ alcohols,

a solvent mixture of C₁-C₆ alcohols and a solvent selected from thegroup consisting of acetonitrile, nitromethane, toluene, methylenechloride and acetic acid.

One factor to be considered in selecting a Lewis acid and solvent is theacid sensitivity of the 7α-substituted steroid (II). The reaction mustbe performed with a Lewis acid and in a solvent where the product isstable as is known to those skilled in the art. It is preferred that thesolvent be a protic solvent, one that has a pK_(a) of less than about19. The reaction can be performed in a temperature range of from about−78° to about 60°; preferably in a temperature range of from about −40°to about −15°. It is more preferred to perform the reaction at about−20°. The reaction normally will take from a few hours to a daydepending on the number of equivalent used and the reaction temperature.

Useful 7α-substituted steroids (II) include those selected from thegroup consisting of:

-   17β-hydroxy-7α-(5′-methyl-2′-furyl)-pregna-4,9-dien-3-one-21-carboxylic    acid, γ-lactone,-   11α,17β-dihydroxy-7α-(5′-methyl-2′-furyl)-pregna-4-en-3-one-21-carboxylic    acid, γ-lactone,-   9α,11α-epoxy-17β-hydroxy-7α-(5′-methyl-2′-furyl)-pregn-4-en-3-one-21-carboxylic    acid, γ-lactone,-   17β-hydroxy-7α-(5′-t-butyl-2′-furyl)-pregna-4,9(11)-dien-3-one-21-carboxylic    acid, γ-lactone,-   11α,17β-dihydroxy-7α-(5′-t-butyl-2′-furyl)-pregn-4-en-3-one-21-carboxylic    acid, γ-lactone,-   11α,17β-dihydroxy-7α-(4′-bromo-2′-furyl)-pregn-4-en-3-one-21-carboxylic    acid, γ-lactone,-   11α,17β-dihydroxy-7α-(4′-methyl-2′-furyl)-pregn-4-en-3-one-21-carboxylic    acid, γ-lactone and-   7α-allyl-17β-hydroxypregna-4,9(11)-dien-3-one, 21-carboxylic acid,    γ-lactone.

Rather than carrying the 7α-substituted steroid (II) on to the next stepin situ, it is preferred to isolate and purify the 7α-substitutedsteroid (II) before performing the next step. The preferred method ofpurification of the 7α-substituted steroid (II) is by crystallization.The process for purifying the 7α-substituted steroid of formula (II)comprises crystallizing the 7α-substituted steroid (II), which containsgreater than 5% of the 7β-isomer from a solvent selected from the groupconsisting of ethyl acetate, n-propyl acetate and butyl acetate. It ispreferred to obtain the 7α-substituted steroid (II) in greater than99.8% isomeric purity and it is preferred that the crystallizationsolvent is n-propyl acetate. Crystallization co-solvents may be used.

The next step in the process of CHART A, is the conversion of the7α-substituted steroid (II) to the corresponding cis-enedione (III-cis),by an oxidative process which comprises (1) contacting the7α-substituted steroid of formula (II) with an agent selected from thegroup consisting of:

(a) a halogenating agent in the presence of water and a base whoseconjugate acid has a pK_(a) of >about 8,

(b) an oxygen donating agent,

(c) electrochemical oxidation,

(d) a quinone in the presence of water or

(e) nonquinone oxidants. It is preferred that the agent be ahalogenating agent.

Useful halogenating agents include those selected from the groupconsisting of dibromodimethylhydantoin, dichlorodimethylhydantoin,diiododimethylhydantoin, N-chlorosuccinamide, N-bromosuccinamide,N-iodosuccinamide, trichloroisocyanuric acid, t-butylhypochlorite and3-bromo-1-chloro-5,5-dimethylhydantoin; it is preferred that thehalogenating is dibromodimethylhydantoin. When using a halogenatingagent, the amount used should be at least one equivalent of thehalogenating agent; preferably from about 1.0 to about 1.05 equivalentsof the halogenating agent are used. It is more preferred that the amountof halogenating agent be about 1.01 equivalents. The reason is that,one-equivalent is required to complete the reaction but any excess needsto be quenched. Suitable quenching agents include bisulfite,isobutylvinyl ether, 2-methylfuran and hypophosphorous acid. Usefuloxygen donating agents include those selected from the group consistingof:

a peracid,

singlet oxygen followed by either phosphite or thiourea,

triplet oxygen,

hydrogen peroxide with a ketone selected from the group consisting ofQ₄-CO-Q₅ where Q₄ and Q₅ are the same or different and are:

-   -   C₁-C₄ alkyl optionally substituted with 1 thru 9 —Cl or —F, and        where the    -   Q₄ and Q₅ are taken together with the attached carbon atom to        form a cyclic ketone of 5 thru 7 members and ketones of the        formula:

hydrogen peroxide in combination with methyltrioxorhenium,

trichloroacetonitrile/hydrogen peroxide,

trichloroacetamide/hydrogen peroxide,

DDQ/water,

p-chloranil/water,

φ—C(CH₃)₂—O—OH or an alkylhydroperoxide in combination with a metalcontaining activator, where alkyl is from C₄-C₁₀ alkyl and metalcontaining activator is selected from the group consisting ofTi(isopropoxide)₄, peroxotungstophosphate, VO(acetylacetonate)₂ and MOhexacarbonyl. It is preferred that the oxygen donating agent is aperacid. Useful peracids include those selected from the groupconsisting of:

(a) perbenzoic acid optionally substituted with 1 or 2 —Cl or —NO₂,

(b) percarboxylic acids of the formula C_(n2)(Q₆)2_(n2+1)—CO₃H where n₂is 1 thru 4 and Q₆ is —H, —Cl or —F,

(c) perphthalic acid and

(d) magnesium peroxyphthalate. An excess oxygen donating agent presentmust also be quenched as was done for the halogenating agents. Base isrequired to neutralize the acid produced during the transformation ofthe 7α-substituted steroid (II) to the cis-enedione (III-cis). Use basesinclude those selected from the group consisting of acetate,bicarbonate, carbonate, propionate, benzoate, dibasic phosphate andborate; it is more preferred that the base be acetate. For example, whenthe halogenating agent is dibromodimethylhydantoin, hydrobromic acid isproduced. Hence, one equivalent of base per equivalent of acid producedis required. In practice, a slight excess is used, about 1.5equivalents. Suitable solvents for this reaction are those which arewater miscible and which dissolves both the 7α-substituted steroid (II)and the halogenating agent or oxygen donating agent. Acetone and THF arepreferred solvents. The reaction is performed at room temperature, about20 to about 25°. The reaction takes a few hours depending on thereactivity of the oxygenating donating agent or halogenating agent. Whenformed, the cis-enedione (III-cis) does not have to be isolated andpurified, but rather can be used in subsequent transformations “as is”or in situ. It is preferred that the cis-enedione (III-cis) is17β-hydroxy-7α-(cis-1′,4′-dioxopent-2′-en-1′-yl)pregna-4,9(11)-dien-3-one-21-carboxylicacid, γ-lactone. Other oxidants useful for transformation of the7α-substituted steroid (II) to the cis-enedione (III-cis) includequinones (listed elsewhere). The 7α-substituted steroid (II) iscontacted with a stoichiometric amount of quinone and at least astoichiometric amount of water in a water-miscible organic solvent. Thecontacting is preferably done at around room temperature. In addition,the oxidation can be accomplished by electrochemistry. Theelectrochemical oxidation is accomplished by contacting the7α-substituted steroid (II) with a sub-stoichiometric amount of aquinone (preferably DDQ) and at least a stoichiometric amount of waterin an electrochemical cell using standard electrochemical techniquessuch as are described in U.S. Pat. No. 4,270,994. Finally, the oxidationcan be accomplished with non-quinone agents which include, manganicacetate, potassium permanganate, ceric ammonium nitrate, iodosobenzene,iodobenzenediacetate, iodobenzenebistrifluoroacetate, chromic acid(“Jones reagent”), and lead tetraacetate. These reactions are typicallyrun in aqueous acetone as solvent at around room temperature (20-250),although many water-miscible organic co-solvents can be used in place ofacetone. Other oxidizing agents that effect this transformation includehydrogen peroxide or an organic hydroperoxide (listed elsewhere) incombination with a metal catalyst such as methyltnoxorhenium, palladiumacetate, ruthenium trichloride, or ruthenium tetroxide. These reactionscan be run in any solvent in which the 7α-substituted steroid (II) issoluble such as methylene chloride, acetone, etc. The reactionsinvolving ruthenium catalysts are preferably run in aqueousacetonitrile.

In the process of CHART A, the cis-enedione (III-cis) can be transformedto the corresponding trans-enedione (III-trans) or it can be convertedto the peroxy compound (IV-OOH), the hydroxy compound (IV-OH), thebiscarbonyl compound (V) or the carboxylic acid (VI) or mixture thereof.When the term carboxylic acid (VI) is used, it refers to and includesthe pharmaceutically acceptable salts thereof. These will include thesodium, potassium, lithium, magnesium, tetrabutylammonium and thecarboxylic acid salts with DBU, tetramethylquanidine, triethylamine andothers. The identity of the particular cation is not important sinceeventually it is lost when forming an acid which ultimately is convertedto the methyl ester (VIII) and eplerenone (IX) which requires a methylester at the 7α-position. It is preferable to convert the cis-enedione(III-cis) to the corresponding trans-enedione (III-trans) rather thanconvert the cis-enedione (III-cis) to a mixture of peroxy (IV-OOH),hydroxy (IV-OH) and biscarbonyl (V) compounds.

When the cis-enedione (III-cis) is transformed to the correspondingtrans-enedione (III-trans), the cis-enedione (III-cis) is contacted withan isomerization catalyst which can be either a chemical agentincluding:

-   -   (a) a strong acid of pK_(a) of <about 2;    -   (b) a tertiary amine whose conjugate acid has a pK_(a)>about 8        and    -   (c) salt of a tertiary amine whose conjugate acid has a        pK_(a)>about 8,    -   (d) I₂,    -   (e) (C₁-C₄)₃P,    -   (f) φ₃P, or a physical agent such as    -   (g) heating to about 80°.

It is preferred that the isomerization catalyst be a strong acid ofpK_(a) of <about 2. When the isomerization catalyst is a strong acid ofpK_(a) of <about 2, useful strong acids of pK_(a) of <about 2 includethose selected from the group consisting of hydrochloric acid,hydrobromic acid, hydroiodoic acid, hydrofluoroic acid, sulfuric acid,phosphoric acid, nitric acid, trichloroacetic acid and trifluoroaceticacid, it is preferred that the strong acid of pK_(a) of <about 2 behydrochloric acid. When the isomerization catalyst is a strong acid ofpK_(a) of <about 2, it is preferred that it be used in anhydrous form orif used in as an aqueous mixture that the reaction be performed as a twophase system with the aqueous phase being separate. When theisomerization catalyst is a tertiary amine whose conjugate acid has apK_(a)>about 8, useful tertiary amines whose conjugate acid has apK_(a)>about 8 include those selected from the group consisting of(Q₃)₃N were Q₃ is C₁-C₃ alkyl, DBU, DBN, DABCO, pyridine,p-dimethylaminopyridine and pyrrolidinylpyridine. When the isomerizationcatalyst is salt of a tertiary amine whose conjugate acid has apK_(a)>about 8, it is preferred that the salt of a tertiary amine whoseconjugate acid has a pK_(a)>about 8 be pyridine hydrochloride.Regardless of which chemical agent is used, only a catalytic amount isrequired. For example, after formation of the cis-enedione (III-cis)just adding commercial chloroform containing the usual impurity ofhydrochloric acid is sufficient to effect the transformation to thecorresponding trans-enedione (III-trans), see EXAMPLE 4, Part 2. Theisomerization of cis-enedione (III-cis) to the correspondingtrans-enedione (III-trans) can be performed at 20-25° (roomtemperature). At room temperature, the reaction usually takes a fewhours. It is necessary to monitor the course of the reaction by standardmethods such as LC or TLC to ensure that it does not go too long. If thereaction goes too long, the reaction reforms the 7α-substituted steroid(II) with a Δ⁶-double bond. Once the reaction has proceeded tocompleteness where it is desirous to terminate the reaction, thereaction can be terminated as follows. When the isomerization catalystis an acid or salt of a tertiary amine whose conjugate acid has a pK_(a)of >8, one can terminate the reaction by washing with water. If aqueousacid is used as the isomerization catalyst, it is best to separate thephases and then wash the non-aqueous phase with water. If theisomerization catalyst is a tertiary amine whose conjugate acid has apK_(a) of >8, then the reaction mixture is washed with aqueous acidfollowed by water. The trans-enedione (III-trans) can be isolated andpurified, however it is preferred not to isolate and purify it butrather carry it on in situ.

In the process of CHART A, the next step is the conversion of either thecis-enedione (III-cis) or trans-enedione (III-trans), or mixturethereof, to the corresponding hydroperoxy (IV-OOH) compound, hydroxy(IV-OH) compound, biscarbonyl (V) compound and/or the carboxylic acid(VI) or mixtures thereof. The cis-enedione (III-cis) or trans-enedioneIII-trans), or mixture there of, is transformed to the correspondinghydroxy compound, peroxy-compound (IV-OOH), or biscarbonyl compound (V)or carboxylic (VI) by contacting the cis-enedione (III-cis) ortrans-enedione (III-trans) or a mixture thereof, with ozone in thepresence of an alcohol of the formula R₇₋₂—OH where R₇₋₂ is —H or C₁-C₄alkyl optionally substituted with one or two —OH. This includes water,methanol, ethanol, propyl alcohol, isopropyl alcohol, ethylene glycol,glycerol, etc. It is preferred that R₇₋₂ is —H, C₁ or is iso-C₃; it ismore preferred that R₇₋₂ is a mixture of —H, C₁ and iso-C₃. This means amixture of water, methanol and isopropanol is the preferred R₇₋₂—OH. Thesteroidal starting materials must be in solution using a solvent thatwill dissolve them at the cold temperatures at which it is preferred toperform this reaction. Methylene chloride is the preferred solvent. Thereaction temperatures can be as low as about −100° up to about 40°. Itis preferred that the temperature be from about −78° to about −20°; itis more preferred that the temperature be about −50°. The lower thetemperature, the more selectivity; the higher the temperature the lessselectivity. Hence, the actual temperature used will depend on theparticular reactants used and the degree of selectivity desired. Thereaction is permitted to run until the starting material is reduced to asmall-amount. The ozone must be stopped when the starting material isconsumed or the ozone will destroy the product by reacting with the Δ⁴-and/or Δ⁹⁽¹¹⁾-double bonds if present. The alcohol, R₇₋₂—OH, is used ina large excess to efficiently trap the carbonyl oxide intermediateproduced. Further, the reaction temperature, the time the reaction ispermitted to run and the nature of the particular alcohol, R₇₋₂—OH,determines the identity of the product or if more than one product isproduced, the ratio of products. If the alcohol, R₇₋₂—OH, has a hinderedR₇₋₂ group, then the product is more likely to be the biscarbonylcompound (V), all other things being equal. Similarly, if the alcohol,R₇₋₂—OH, does not have a hindered R₇₋₂ group, such as methyl, then theproduct is more likely to be the hydroxy compound (IV-OH), all otherthings being equal. The preferred product produced by the oxidationprocess is the carboxylic acid (VI).

The hydroperoxy compound (IV-OOH) can be converted to the correspondinghydroxy compound (IV-OH) by contacting the hydroperoxy compound (IV-OOH)with a hydroperoxy-deoxygenating agent. It is preferred to use a mildhydroperoxy-deoxygenating agent, one which both deoxygenates, and seconddoes not add to the steroid molecule. Useful hydroperoxy-deoxygenatingagents include those selected from the group consisting of:

Q₁Q₂S where Q₁ and Q₂ are the same or different and are C₁-C₄ alkyl orphenyl,

bisulfite,

sulfite,

thiosulfate,

tetrahydrothiophene,

hydrosulfite,

thiourea,

butyl vinyl ether,

(C₁-C₄ alkyl)₃ phosphine,

triphenylphosphine, and

tetramethylethylene. It is preferred that the hydroperoxy-deoxygenatingagent is dimethylsulfide. When the hydroperoxy-deoxygenating agent isbisulfite and sulfite, sodium and potassium are the preferred cations.One equivalent of the hydroperoxy-deoxygenating agent is required, butmore then one equivalent, such as about two equivalents, are normallyused to ensure that all of the hydroperoxy compound (IV-OOH) is reduced.The reaction is performed at 20-25° and is usually complete in about 1hour. The hydroxy compound (IV-OH) can be isolated and purified ifdesired, however, it is preferable to carry it on in situ withoutisolating or purifying it. It is preferred that the hydroxy compound(IV) is17β-hydroxy-7α-(1′-oxo-2′-isopropoxy-2′-hydroxy-ethyl)pregna-4,9(11)-dien-3-one-21-carboxylicacid, γ-lactone.

The hydroperoxy compound (IV-OOH) can be transformed to thecorresponding carboxylic acid (VI) by contacting the hydroperoxycompound (IV-OOH) with a-carboxylic acid forming agent selected from thegroup consisting of:

(a) heat,

(b) a base whose conjugate acid has a pK_(a) of about 5 or above,

(c) an acid which has a pK_(a) of less than about 3,

(d) an acylating agent. When the carboxylic acid forming agent is (a)heat, the reaction mixture should be heated to the range of from about30° to about 120°; preferably from about 80° to about 90°. When thecarboxylic acid forming agent is, (b) a base whose conjugate acid has apK_(a) of about 5 or above, useful bases include inorganic basesselected from the group consisting of hydroxide, bicarbonate, andcarbonate and organic bases selected from the group consisting of (Q₃)₃Nwere Q₃ is C₁-C₃ alkyl, DBU, DBN, DABCO, pyridine andp-dimethylaminopyridine. It is preferred that the base is bicarbonate.Sufficient base is necessary to neutralize the steroid acid produced andany additional acid by-products. When the carboxylic acid forming agentis, (c) an acid which has a pK_(a) of less than about 3, useful acidsinclude those selected from the group consisting of hydrochloric acid,sulfuric acid, phosphoric acid, nitric acid and organic acids of theformula of R_(acid-1)—COOH where R_(acid-1) is —H and C₁-C₃ alkyloptionally substituted with 1 thru 3 —Cl and —F; preferred are formicacid and trifluoroacetic acid. While catalytic amounts of acid aresufficient, several equivalent are preferred. When the carboxylic acidforming agent is, (d) an acylating agent, useful acylating agents areselected from the group consisting of R_(acid-2)—CO—O—CO—R_(acid-2)where R_(acid-2) is

—H,

C₁-C₃ alkyl optionally substituted with 1 thru 3 —Cl and —F and

—φ. It is preferred that acylating agent is acetic anhydride ortrifluoracetic anhydride. One equivalent of the acylating agent isrequired. When using an acylating agent, it is preferred to use it withan acylation catalyst. Preferred acylation catalysts are pyridine andp-dimethylaminopyridine (DMAP). With regard to solvents, it is importantto perform the process under homogenous reaction conditions to avoiddecomposition of the hydroperoxy compound (IV-OOH). This means using onephase conditions. Therefore, the solvent of choice will depend on thecarboxylic acid forming agent used. If the carboxylic acid forming agentrequires water to dissolve the reagent such as when the carboxylic acidforming agent is bicarbonate, then a water miscible organic solvent suchas acetone, methanol, DMF or isopropanol is required. If the carboxylicacid forming agent is pyridine then the organic solvent can be a waterimmiscible organic solvent such as acetonitrile, methylene chloride orethyl acetate. Hence, the selection of the solvent depends on the natureof the carboxylic acid forming agent used as is know to those skilled inthe art. With the exception of the carboxylic acid forming agent (a)heat, the other acid forming agents (b), (a) and (d) can all be reactedat 20-25°. The reaction is quite fast and is usually over in less thanone hour.

Both the hydroxy compound (IV-OH) and the biscarbonyl compound (V) areconverted to the corresponding carboxylic acid (VI) in the same manner.The process involves contacting the hydroxy compound (IV-OH) or thebiscarbonyl compound (V), or mixture thereof, with an oxidativelycleaving agent. Useful oxidatively cleaving agents are selected from thegroup consisting of:

(1) hydrogen peroxide with a carboxylic acid forming agent selected fromthe group consisting of:

-   -   (a) heat,    -   (b) a base whose conjugate acid has a pK_(a) of about 5 or        above,    -   (c) an acid which has a pK_(a) of less than about 3,    -   (d) an acylating agent and an acylation catalyst;

(2) KHSO₅;

(3) hydrogen peroxide with a ketone selected from the group consistingof Q₄-CO-Q₅ where Q₄ and Q₅ are the same or different and are:

-   -   C₁-C₄ alkyl optionally substituted with 1 thru 9 —Cl or —F,    -   where the Q₄ and Q₅ are taken together with the attached carbon        atom to form a cyclic ketone of 5 thru 7 members, and ketones of        the formula:

(4) hydrogen peroxide in combination with methyltrioxorhenium,

(5) φ—C(CH₃)₂—O—OH or an alkylhydroperoxide in combination with a metalcontaining activator, where alkyl is from C₄-C₁₀ alkyl and metalcontaining activator is selected from the group consisting ofTi(isopropoxide)₄, peroxotungstophosphate, VO(acetylacetonate)₂ and Mohexacarbonyl;

(6) peracids selected from the group consisting of

-   -   (a) perbenzoic acid optionally substituted with 1 or 2 —Cl or        —NO₂,    -   (b) percarboxylic acids of the formula C_(n2)(Q₆)2_(n2+1)—CO₃H        where n₂ is 1 thru 4 and Q₆ is —H, —Cl or —F,    -   (c) perphthalic acid,    -   (d) magnesium peroxyphthalate. It is preferred that the        oxidatively leaving agent is hydrogen peroxide with a carboxylic        acid forming agent. When the carboxylic acid forming agents        are (a) heat, (b) a base whose conjugate acid has a pK_(a) of        about 5 or above (c) an acid which has a pK_(a) of less than        about 3 or (d) an acylating agent and an acylation catalyst,        they should be used in the same manner as discussed above for        the transformation of the hydroperoxy compound (IV-OOH) to the        corresponding carboxylic acid (VI). As stated above, one        equivalent of the oxidatively cleaving agent is required. Two        equivalents are normally used and the reaction is monitored so        that when the reaction nears completion it is stopped, or        quenched, and worked up before the oxidatively cleaving agent        attacks the Δ⁴- and and/or Δ⁹⁽¹¹⁾-steroid double bonds. Hydrogen        peroxide and bicarbonate are preferred as the oxidatively        cleaving agent. With regard to solvents it is important to        perform the process under homogenous reaction conditions,        meaning one phase conditions. Therefore, the solvent of choice        will depend on the oxidatively cleaving agent used. If the        carboxylic acid forming agent requires water to dissolve the        reagent such as when the carboxylic acid forming agent is        bicarbonate, then a water miscible organic solvent such as        acetone, DMF, methanol or isopropanol is required. If the        carboxylic acid forming agent is pyridine then the organic        solvent can be a water immiscible organic solvent such as        acetonitrile, methylene chloride or ethyl acetate. Hence, the        selection of the solvent depends on the nature of the carboxylic        acid forming agent used as is known to those skilled in the art.        With the exception of the carboxylic acid forming agent (a)        heat, the other acid forming agents (b), (c) and (d) can all be        reacted at 20-25°. The reaction is quite fast and is usually        over in less than one hour. It the reaction mixture contains        some hydroperoxy compound (IV-OOH), then it is useful to first        treat the reaction mixture with a hydroperoxy-deoxygenating        agent. It is preferred that the hydroperoxy-deoxygenating agent        is dimethylsulfide.

There are a number of processes to transform a carboxylic acid (VI) tothe corresponding 5,7-lactone (VII), where the C- and D-rings of thestarting carboxylic acid (VI) and product 5,7-lactone are the same. Theprocesses differ depending on the nature of the steroid A-/B-rings ofthe starting carboxylic acid (VI). They use different reactants andproduce 5,7-lactones (VII) with different steroid A-/B-rings. One ofthese processes produces a 5,7-lactone of formula (VII)

where

-   -   (Va) R₂ is —H:—H; R₃ is ═O; R₄ is —H:—H;    -   (Vb) R₂ is —H:—H; R₃ is R_(3a):R_(3b) where both R_(3a) and        R_(3b) are —OH and R₄ is —H:—H;

where R₉, R₁₁ and R₁₁ are as defined above, which comprises:

(1) contacting a carboxylic acid of formula (VI)

where

-   -   (I) R₃ is ═O; R₄ is R₄₋₁:R₄₋₂ where one of R₄₋₁ and R₄₋₂ is —H        and the other of R₄₋₁ and R₄₋₂ is taken together with R₅ to form        a second bond between the carbon atoms to which they are        attached; R₆ is —H:—H;    -   (III) R₃ is α-R₃₋₅:β-R₃₋₆ where R₃₋₅ is —O—R₃₁ and R₃₋₆ is O—R₃₂        where R₃₁ and R₃₂ are the same or different and are selected        from the group consisting of

C₁-C₃ alkyl and

R₃₁ and R₃₂ are taken with the attached —O—C—O— to form a cyclic ketalof 5 or 6 atoms of the formula—(CH₂)—(CR₃₃R₃₄)_(n1)—(CH₂)—

where n₁ is 0 or 1;

where R₃₃ and R₃₄ are the same or different and are —H and C₁, —C₃alkyl; R₄ is —H:—H; R₆ is R₆₋₅:R₆₋₆ where one of R₆₋₅ and R₆₋₆ is takentogether with R₅ to form a second bond between the carbon atoms to whichthey are attached and the other of R₆₋₅ and R₆₋₆ is —H;

-   -   (IV) R₃ is α-R₃₋₇:β-R₃₋₈ where R₃₋₇ is —O—R₃₁ and R₃₋₈ is —O—R₃₂        where R₃₁ and R₃₂ are as defined above; R₄ is R₄₋₇:R₄₋₈ where        one of R₄₋₇ and R₄₋₈ is taken together with R₅ to form a second        bond between the carbon atoms to which they are attached and the        other of —R₄₋₇ and R₄₋₈ is —H; R₆ is —H:—H;

where R₉, R₁₁ and R₁₇ are as defined above; with a reaction medium whichhas a pH of less than about 5. The conversion of the carboxylic acid(VI) to the corresponding 5,7-lactone (VII) is an equilibrium reaction.The lower the pH used for the reaction medium the more the equilibriumshifts toward the 5,7-lactone (VII), hence the desire to keep the pHless than 5 and preferably in the range of 1 thru 5. It is preferred toperform the reaction under anhydrous conditions; under anhydrousconditions it is preferred that the acid be a strong acid of pK_(a) lessthan about 2. Useful strong acids include those selected from the groupconsisting of fluorosulfonic, chlorosulfonic, benzenesulfonic,p-toluenesulfonic, methanesulfonic, trifluoromethanesulfonic,trifluoroacetic, trichloroacetic, hydrochloric, sulfuric, phosphoric andnitric; it is preferred that the acid is benzenesulfonic,p-toluenesulfonic or methanesulfonic acid. Alternatively, the processcan be performed using aqueous acid as the catalyst. Under theseconditions it is preferred to perform the process in a two-phase system.The amount of acid used in not very important and can be present in anamount from catalytic to excess. Bases are also operable to catalyze thereaction of the carboxylic acid (VI) to the corresponding 5,7-lactone(VII) as long as they are used in a catalytic amount. Useful basesinclude those selected from the group consisting of hydroxide,bicarbonate, carbonate, DBU, DBN, DABCO, pyridine,p-dimethylaminopyridine, Q₇-COO⁻ where Q₇ is —H, C₁-C₃ alkyl or —φ,(Q₃)₃N where Q₃ is C₁-C₃ alkyl; preferred are hydroxide, bicarbonate,carbonate, triethylamine or pyridine. The solvents for thetransformation of the carboxylic acid (VI) to the corresponding5,7-lactone (VII) are helpful in effecting the equilibrium of thereaction. It is preferred to use a solvent in which the startingcarboxylic acid (VI) is soluble and in which the 5,7-lactone (VII) isnot soluble. That way the 5,7-lactone (VII) precipitates out as it isformed pushing the equilibrium towards the desired 5,7-lactone (VII). Apreferred solvent is acetone. This reaction is performed from about 0°to about 25° and is complete in a few hours. Depending on the pH of thereaction medium and solvent used, ratios of <95/5 of carboxylic acid(VI)/5,7-lactone (VII) are obtained. Since this process step is anequilibrium reaction, the pH of the reaction medium helps control thefinal position of the equilibrium as is known to those skilled in theart.

A second process for producing a 5,7-lactone of formula (VII)

where

-   -   (Va) R₂ is —H:—H, R₃ is ═O and R₄ is —H:—H;

where R₉, R₁₁ and R₁₇ are as defined above, comprises:

(1) contacting a carboxylic acid of formula (VI)

where

(I) R₃ is ═O; R₄ is R₄₋₁:R₄₋₂ where one of R₄₋₁ and R₄₋₂ is —H and theother of R₄₋₁ and R₄₋₂ is taken together with R₅ to form a second bondbetween the carbon atoms to which they are attached; R₆ is —H:—H;

where R₉, R₁₁ and R₁₇ are as defined above; under anhydrous conditionswith an anhydrous reaction medium of pH less than about 5. It ispreferred that the reaction medium contains an acid which has a pK_(a)of <about 4. Useful acids which have a pK_(a) of <about 4 include thoseselected from the group consisting of fluorosulfonic, chlorosulfonic,benzenesulfonic, p-toluenesulfonic, methanesulfonic,trifluoromethanesulfonic, trifluoroacetic, trichloroacetic,hydrochloric, sulfuric, phosphoric and nitric. It is preferred that theacid is benzenesulfonic, p-toluenesulfonic or methanesulfonic. It isalso preferred that the carboxylic acid (VI) is reacted with the acid ina two-phase system. The process also includes reacting the carboxylicacid (VI) with a catalytic amount of base. Useful bases include thoseselected from the group consisting of hydroxide, bicarbonate, carbonate,DBU, DBN, DABCO, pyridine, p-dimethylaminopyridine, Q₇-COO⁻ where Q₇ is—H, C₁-C₃ alkyl or —φ, (Q₃)₃N where Q₃ is C₁-C₃ alkyl.

A third process for producing a 5,7-lactone of formula (VII)

where

-   -   (Vc) R₂ is —H:—H, R₃ is —O—R_(3a):—O—R_(3b) where R_(3a) and        R_(3b) the same and are C₁-C₃ alkyl or where R_(3a) and R_(3b)        are taken together with the attached —O—C—O— to form a cyclic        ketal of 5 or 6 atoms of the formula        —(CH₂)—(CR₃₃R₃₄)_(n1)—(CH₂)—

where n₁ is 0 or 1;

where R₃₃ and R₃₄ are the same or different and are —H and C₁-C₃ alkyl,and R₄ is —H:—H;

(VI) R₂ is —H:—H; R₃ is R_(3c):R_(3d) and R₄ is R_(4c):R_(4d) where oneof R_(3c) and R_(3d) is taken with one of R_(4c) or R_(4d) to form asecond bond between the carbon atoms to which they are attached and theother of R_(3c) and R_(3d) is CH₃—O— or C₂H₅—O—;

and the other of R_(4c) and R_(4d) is —H; or

(VII) R₂ is R_(2e):R_(2f) and R₃ is R_(3e):R_(3f) where one of R_(2e)and R_(2f) is taken with one of R_(3e) or R_(3f) to form a second bondbetween the carbon atoms to which they are attached and the other ofR_(2e) and R_(2f) is —H, and the other of R_(3e) and R_(3f) is CH₃—O— orC₂H₆—O—; or mixtures thereof;

where R₉, R₁₁ and R₁₇ are as defined above, comprises:

(1) contacting a carboxylic acid of formula (VI)

where

-   -   (III) R₃ is α-R₃₋₅:β-R₃₋₆ where R₃₋₅ is —O—R₃₁ and R₃₋₆ is        —O—R₃₂ where R₃₁ and R₃₂ are the same or different and are        selected from the group consisting of

C₁-C₃ alkyl and

R₃₁ and R₃₂ are taken with the attached —O—C—O— to form a cyclic ketalof 5 or 6 atoms of the formula—(CH₂)—(CR₃₃R₃₄)_(n1)—(CH₂)—

where n₁ is 0 or 1;

where R₃₃ and R₃₄ are the same or different and are —H and C₁-C₃ alkyl;R₄ is —H:—H; R₆ is R₆₋₅:R₆₋₆ where one of R₆₋₅ and R₆₋₆ is takentogether with R₅ to form a second bond between the carbon atoms to whichthey are attached and the other of R₆₋₅ and R₆₋₄ is —H—;

(IV) R₃ is α-R₃₋₇:β-R₃₋₈ where R₃₋₇ is —O—R₃₁ and R₃₋₈ is —O—R₃₂ whereR₃₁ and R₃₂ are as defined above; R₄ is R₄₋₇:R₄₋₈ where one of R₄₋₇ andR₄₋₇ is taken together with R₅ to form a second bond between the carbonatoms to which they are attached and the other of R₄₋₇ and R₄₋₈ is —H;R₆ is —H:—H;

where R₉, R₁₁, and R₁₇ are as defined above; with at least a-catalyticamount of acid. It is preferred that the acid have a pK_(a) of <about 4and are as discussed above.

The present invention includes a process for the preparation of a methylester of formula (VIII)

where

-   -   (I) R₃ is ═O; R₄ is R₄₋₁:R₄₋₂ where one of R₄₋₁ and R₄₋₂ is —H        and the other of R₄₋₁ and R₄₋₂ is taken together with R₅ to form        a second bond between the carbon atoms to which they are        attached; R₆ is —H:—H;

where R₉, R₁₁, and R₁₇ are as defined above, which comprises:

(1) contacting a 5,7-lactone of the formula (VII)

where R₄ is —H:—H and where R₃, R₉, R₁₁ and R₁₇ are defined above, withbase, and

(2) contacting the reaction mixture of step (1) with a methylatingagent. The base needs to be strong enough to open the 5,7-lactone (VII)but of the type that will not react with the methylating agent, a weaknucleophile. Useful bases include those selected from the groupconsisting of bicarbonate, carbonate, hydroxide and R_(base)O⁻ whereR_(base) is C₁-C₄ alkyl. It is preferred that the base is bicarbonate.The amount of base required is from about 1 to about 1.5 equivalents.Useful methylating agents include those selected from the groupconsisting of dimethylsulfate, methyl iodide, methyl bromide,trimethylphosphate, dimethylcarbonate and methyl chloroformate;preferred is dimethylsulfate. The amount of methylating agent usedshould be the same as the number of equivalents of base used or a veryslight excess over that. The preferred method of the process is to reactit in a sequential manner in a two-step reaction with base first andthen the methylating agent. If the reaction is performed all in onestep, the base reacts with the methylating reagent necessitating theneed for more base and more methylating agent. The more efficient way isto first react the 5,7-lactone (VII) with at least one equivalent ofbase, preferably from about 1 to about 1.5 equivalents and then to reactthe salt of the carboxylate acid (VI) which is formed with themethylating agent. The solvent used will depend on the nature of thebase used. If it is water soluble, such as bicarbonate or hydroxide,then a mixture of water and a water miscible organic solvent ispreferred. These water miscible organic solvents include, methanol,ethanol, isopropanol, acetone, THF and DMF. If the base is water solubleand the solvent is a mixture of water and a water immiscible-solvent,then a phase transfer catalyst, such as tetrabutylammonium bisulfate ortributylmethylammonium chloride is used. If the base is soluble in awater immiscible organic solvent, one that will also dissolve the5,7-lactone (VII), then a water-immiscible organic solvent is suitable.The reaction temperature is dependent on the reactivity of themethylating agent. If an agent such as dimethylcarbonate is used thereaction will go slow and heat up to about 150° may be necessary. On theother hand, if a more reactive agent such as dimethylsulfate is used thereaction goes in about 1 hour at 40°. While in theory one equivalent ofbase and one equivalent of methylating agent should be sufficient, inpractice more than one equivalent is needed for the optimum reactionconditions.

The 5,7-lactone (VII) can be transformed to the (salt of the)corresponding-carboxylic acid (VI) by contacting the 5,7-lactone offormula (VII), with a reaction medium which as a pH>7. The reaction issimilar to the transformation of the 5,7-lactone (VII) to the methylester (VIII) except that no methylating agent is used. Since only baseis used, the product produced is the salt of the carboxylic acid (VI).Further, since no methylating agent is present, the amount of base usedis not critical. If the acid form of the carboxylic acid (VI), isdesired the salt form can be acidified to produced the correspondingacid form of the carboxylic acid (VI) as is known to those skilled inthe art.

There are numerous alternative routes using the present invention as setforth in CHART A as will be explained below and is known to thoseskilled in the art. For example, the steroid A-ring can be protected, ascompound (I-P), see CHART B and the explanation below, during thetransformation of (I) to (II) or used in the unprotected form (I).Further, the C- and D-rings can have a variety of functionality duringthe various steps of the process. The C-ring functionality includes, forexample, 9α-hydroxy, 9α-O-(HYDROXY PROTECTING GROUP), 9α-F, 11-keto,11-saturated, 11α-hydroxy, 11α-O-(HYDROXY PROTECTING GROUP),11β-hydroxy, 11β-O-(HYDROXY PROTECTING GROUP), Δ⁹⁽¹¹⁾- and 9α,11α-epoxy.The D-ring functionality includes, for example, 17-keto, 17β-hydroxy,17α-ethynyl-17β-hydroxy, 17α-cyano-17β-hydroxy, 17α-C≡C—CH₂—O—(—H orsubstituted silyl)-17β-OH, 17α-C≡C—CH₂—O—(HYDROXY PROTECTINGGROUP)-17β-O—CH₂H, 17α-CH₂—CH₂—CH₂—OH-17β-OH, 17α-CH₂—CH₂—CH₂—O-(HYDROXYPROTECTING GROUP)-17β-OH, 17α-hydroxy-17β-CO—CH₃, 17β-CO—CH₂—OH,17β—CO—CH₂—O—CO—(CH₂)₀₋₃—CH₃; 17β—O—CH₂-17α resulting in a three memberepoxide, γ-lactone and —O—CH(OR₁₇₋₉)—CH₂—CH₂ . . . where the bond fromthe oxygen (—O) is one of the four bonds at C-17 in the β-configurationand the bond from the methylene group (CH₂ . . . ) is another of thefour bonds at C-17 in the α-configuration to form a 5 member heterocyclecontaining one oxygen atom, where R₁₇₋₉ is —H or C₁-C₃ alkyl. However,the D-ring functionality for the compounds of the processes of claims539, 548 and 556 does not include R₁₇₋₂ being hydroxyl. HYDROXYPROTECTING GROUPs are well known to those skilled in the art. The sameHYDROXY PROTECTING GROUPs are operable at C-9, C-11 and C-17 and areselected from the group consisting of: —Si(—CH₃)₃, —Si(—CH₂CH₃)₃,CO—CH₃, —CO—H and —SiH(CH₃)₂.

At some point the A-ring, if it is not already the required Δ⁴-3-ketofunctionality, must be transformed to the Δ⁴-3-keto functionality.Likewise, with the C-ring, if it is not already the required9α,11α-epoxide functionality, it must be transformed to the9α,11α-epoxide. Similarly, if the D-ring is not already the requiredγ-lactone, it must be transformed to the γ-lactone. However, thosetransformations can take place either before, during or after variousother processes and/or steps of CHART A. It is preferred to start withthe A-ring with Δ⁴-3-keto functionality, the C-ring withΔ⁹⁽¹¹⁾-functionality and the D-ring as the γ-lactone. With regard to theC-ring, it is preferred to maintain the Δ⁹⁽¹¹⁾-functionality throughoutthe process of the invention until the —CO—O—CH₃ group is fullysynthesized at the 7α-position and then transform theΔ⁹⁽¹¹⁾-functionality to the corresponding 9α,11α-epoxide. With regard tothe C-ring one could start with a 11-keto functionality and at somepoint in the process reduce it to the 11α-hydroxy functionality and thenat some later point dehydrate the 11α-hydroxy functionality to thecorresponding Δ⁹⁽¹¹⁾-olefin functionality by either the processes ofEXAMPLEs 18-20 using PCl₅ or by the process of EXAMPLE 31 usingN-(1,1,2,2,3,3,3) hexafluorbpropyldiethyl-amine which is known asIshikawa reagent. There is a thorough discussion below as to how thedehydration of an 11α-hydroxy steroid should be performed using theIshakawa reagent to produce the corresponding Δ⁹⁽¹¹⁾-olefin. If thedehydration of the 11α-hydroxy to the corresponding Δ⁹⁽¹¹⁾-olefin takesplace with a 5′-methyl-2′-furyl substituent at C-7α, with a formula (II)compound, it appears PCl₅ is preferred, but if the dehydration takesplace on the methyl ester (VII), then the Ishikawa reagent is preferred.The Δ⁹⁽¹¹⁾-olefin is then converted to the desired 9α,11α-epoxidefunctionality by means well known to those skilled in the art. Likewise,with regard to the D-ring, one need not start with the γ-lactone in theΔ^(4,6)-3-keto steroid or ketal thereof (l) starting material. One-couldstart with 17-keto or 17β-hydroxy, etc and then at a desired pointcovert the starting D-ring 17-functionality to the desired γ-lactone.The preferred process including what functionality is desired to startwith, and where the conversions are made, is set forth in CHART E. Inshort, it is desired to start with the same functionality as is desiredin the end product for the A-ring and D-rings. It is preferred to startwith the C-ring having the Δ⁹⁽¹¹⁾-olefin functionality which istransformed to the desired 9α,11α-epoxide functionality after the7α-substitutent is finalized as C—O—CH₃. However, as explained above andis known to those skilled in the art, there are numerous alternativeways of preparing eplerenone by the process of CHART A starting withdifferent functionality in the A-, C- and D-rings.

CHART B discloses a process to produce the protected Δ^(4,6)-ketalsteroid (I-P), from the corresponding Δ^(3,5)-3-alkyl enol ethers whichare readily available from the corresponding Δ⁴-3-keto steroids byprocesses known to those skilled in the art. It is preferred use theunprotected Δ^(4,6)-3-keto steroid (I) as the starting material in theprocess of CHART A. However, steroidal Δ^(4,6)-3-ketals (I-P) can alsobe used as the starting material of the process of CHART A. In theprocess of CHART B, the Δ^(4,6)-3-ketal steroid (I-P)

where R₃₁ and R₃₂

(1) the same or different and are C₁-C₃ alkyl, and

(2) taken with the attached O—C—O— to form a cyclic ketal of 5 or 6atoms of the formula—(CH₂)—(CR₃₃R₃₄)_(n1)—(CH₂)—

-   -   where n₁ is 0 or 1;    -   where R₃₃ and R₃₄ are the same or different and are        -   —H,        -   C₁-C₃ alkyl,            is produced from the corresponding Δ^(3,5)-3-alkyl enol            ether

where R³ is

C₁-C₃ alkyl,

CH₃—CO—,

φ—CO— or

R_(Si-1)R_(Si-2)R_(Si-3)Si— where R_(Si-1), R_(Si-2) and R_(Si-3) arethe same or different and are C₁-C₄ alkyl; by contacting theΔ^(3,5)-3-alkyl enol ether (Alkyl enol ether) with a hydride abstractorand an alcohol selected from the group consisting of alcohols of theformula:

(a) R₃₁—OH, where R₃₁ is as defined above,

(b) R₃₂—OH, where R₃₂ is as defined above,

(c) HO—(CH₂)—(CR₃₃R₃₄)_(n1)—(CH₂)—OH where n₁, R₃₃ and R₃₄ are asdefined above,

(d) HO—CH₂—CH₂—OH, by (1) contacting the Δ^(3,5)-3-enol ether (3-alkylenol ether).

Useful hydride abstractors include those selected from the groupconsisting of

DDQ,

p-chloranil,

o-chloranil,

Mn⁺³, Mn⁺⁷, Pb⁺⁴, Pd⁺², Ru⁺⁸, Cr⁺⁶,

o-iodoxybenzoic acid,

o-iodoxybenzoic acid complex with DMSO,

o-iodoxybenzoic acid complex with

-   -   4-methoxypyridine-N-oxide,    -   N-methylmorpholine-N-oxide,    -   trimiethylamine-N-oxide,

iodic acid (HlO₃),

iodine pentoxide (I₂O₅),

ceric ammonium nitrate,

iodosobenzene,

iodobenzenebistrifluoroacetate,

iodobenzenediacetate,

tritylfluoroborate, and by electrochemical oxidation with a catalyticamount of a hydride abstractor. It is preferred that the hydrideabstractor is p-chloranil or DDQ, more preferably DDQ. One equivalent ofthe hydride abstractor is required; more is not harmful, just wasteful.It is preferred that the alcohol is neopentylglycol also known asdimethylpropyleneglycol or 2,2-dimethyl-1,3-propanediol. The solventneeds to dissolve the 3-alkyl enol ether (3-alkyl enol ether) startingmaterial. Suitable solvents include methylene chloride, acetonitrile,THF, and the alike. The reaction is operable in the temperature range ofabout −78° to about 40°, preferred is about −15°. The reaction is veryrapid and is complete in a few minutes at −15°. The entire process ispreferably performed under essentially anhydrous conditions. The term“hydride abstractor” as used herein means the reagent effects the netremoval of one of the hydrogen atoms at C-7 of the 3-dienol ether, anddoes not imply any mechanism by which this removal occurs. It ispreferred that the a Δ^(4,6)-ketal (I-P) is selected from the groupconsisting of

-   17β-hydroxypregna-4,6,9(11)-trien-3-one-21-carboxylic acid,    γ-lactone, cyclic 3-(2′,2′-dimethyl-1′,3′-propanediyl ketal),-   17β-hydroxypregna-4,6,9(11)-trien-3-one-21-carboxylic acid,    γ-lactone, cyclic 3-ethanediyl ketal.

CHART C discloses that the 7α-substituted steroid (II) can also betransformed to the corresponding cis-oxyenedione (X-cis) by (1)contacting the 7α-substituted steroid (II) with ozone in the presence ofa C₁-C₄ alcohol and (2) contacting the mixture of step (1) with ahydroperoxy-deoxygenating agent. The preferences for R₇₋₁, X₁ R_(b),R_(c), R_(d) and the other variable substituents are as set forth aboveas previously stated. The 7α-substituted steroid (II) is dissolved in asuitable C₁-C₄ alcohol, or mixture thereof. It is preferred that theC₁-C₄ alcohol is a C₁ and C₃ alcohols; it is more preferred the alcoholis a C₁ alcohol. Cosolvents such as methylene chloride can also be usedif necessary. The nature of the solvent/co-solvent is not critical aslong as it will dissolve the reactants at the cold temperature at whichthe process is performed. The nature of the alcohol is not critical asit is eventually lost from the steroid molecule. The reactiontemperatures can be as low as about −100° up to about 40°. It ispreferred that the temperature be from about −78° to about −20°; it ismore preferred that the temperature be about −50°. Ozone is passed thruthe reaction mixture as is known to those skilled in the art until theprocess of step (1) is complete. The course of the reaction is monitoredas is known those skilled in the art. When the reaction of step (1) iscomplete, the reaction mixture of step (1) is contacted with ahydroperoxy-deoxygenating agent. It is preferred that thehydroperoxy-deoxygenating agent is trimethylphosphite. It is realizedthat for other processes of this invention the preferredhydroperoxy-deoxygenating agent was dimethylsulfide, but here thepreferred agent is trimethylphosphite. The reaction mixture is thenslowly permitted to warm to 20-250. The reaction will proceed rapidlywhen it reaches the correct temperature for the particular7α-substituted steroid (II). The cis-oxyenedione (X-cis) product can becarried along without isolation and purification if desired.

CHART C further discloses that the cis-oxyenedione (X-cis) can betransformed to the corresponding trans-oxyenedione (X-trans). Theprocess is performed in the same manner and same way that thecis-enedione (III-cis), of CHART A, was transformed to the correspondingtrans-enedione (III-trans).

The cis-oxyenedione (X-cis) or the trans-oxyenedione (X-trans), or amixture thereof, can be transformed to the corresponding hydroperoxycompound (IV-OOH), and/or hydroxy compound (IV-OH), and/or biscarbonylcompound (V) and/or carboxylic acid (VI) or mixture thereof in the samemanner and same way as the cis-enedione (III-cis) or the trans-enedione(III-trans), or a mixture thereof, was transformed to the correspondinghydroperoxy compound (IV-OOH), and/or hydroxy compound (IV-H), and/orbiscarbonyl compound (V) and/or carboxylic acid (X) or mixture thereof.The hydroperoxy compound (IV-OOH), and/or hydroxy compound (IV-OH),and/or biscarbonyl compound (V) and/or carboxylic acid (X) or mixturethereof are then transformed to eplerenone (IX) in the same manner andsame was as previously discussed for the process of CHART A.

The cis-oxyenedione (X-cis) or the trans-oxyenedione (X-trans), or amixture thereof, can be transformed to the corresponding carboxylic acid(VI) by reaction with an oxidatively cleaving agent in the same mannerand same way as the hydroxy compound (IV-OH), and/or biscarbonylcompound (V) are transformed to the corresponding carboxylic acid (VI).

CHART D sets forth the preferred process of the invention (when R₇₋₁ is-A1) with regard to the steroid A-/B-ring, that the steroid A-ring isnot protected. However, given the different variable substituents of thesteroid C- and D-rings and combinations of variable substituentspossible, in some cases it may be preferred to protect the steroidA-ring as would be apparent to one skilled in the art. But in general,it is preferred that the steroid A-ring not be protected and thepreferred process be that of CHART D.

CHART E sets forth the preferred process of the invention with thepreferred variable substituents for each intermediate for the conversionof the Δ^(4,6)-3-keto steroid (I) to eplerenone (IX).

CHART F discloses the reversible nature of the conversion of thecarboxylic acid (VI) with the 5,7-lactone (VII).

CHART G discloses the general process of the invention when the adduct—R₇₋₁ is the cyclic adduct (-A2). The 7α-substituted steroid (II) isformed in the same manner as discussed above for CHART A when the adductis (-A1). Then the α-substituted steroid (II) where R₇₋₁ is (-A2) isreacted in the same way, with the same reagents as used in CHART A for(-A1) to give intermediates of the same type as the intermediates ofCHART A for adduct (-A1). The processes of CHARTs A and G are analogous,the reactants are the same and used in the same order. The intermediatesproduced are either isomers or homologs of each other.

CHART H discloses the general process of the invention when the adductR₇₋₁ is (-B), (-C), (-D1), (-D2) and (-D3). The process of CHART H is atwo step process. The first step of the process is to transform theΔ^(4,6)-3-keto steroid or ketal thereof (I) starting material to thecorresponding 7α-substituted steroid (II) where R₇₋₁ is a substituentselected from the group consisting of—CR_(b2)=M  (-B)—C≡C—R_(c2)  (-C)—CH₂CH═CH₂  (-D1)—CH═C═CH₂  (-D2)—CH₂—C≡C—H  (-D3)The second step is oxidative cleavage of the 7α-substitutent to give acarboxylic acid functionality, —CO—OH of the carboxylic acid (VI). Inthe olefinic substituent (-B), “M” is a group which forms a double bondwith carbon and is restricted to carbon, nitrogen and oxygen. Thesubstituent R_(b2) is a group that can be transformed into a hydroxylgroup by either oxidation or hydrolysis. With the acetylenic substituent(—C),the group R_(c2) can be virtually any group since it is ultimately lostwhen the triple bond is cleaved to a carboxylic acid (VI). Likewise withthe three-carbon unsaturated substituents (-D1), (-D2) and (-D3), two ofthe three carbon atoms are cleaved oxidatively, leaving a carboxylicacid group. In transforming the Δ^(4,6)-3-keto steroid or ketal thereof(I) starting material to the corresponding 7α-substituted steroid (II),the Δ^(4,6)-3-keto steroid or ketal thereof (I) starting material isreacted with the nucleophile selected from the group consisting of

(d) of the formula (B)R_(a)—CE₁=M  (B)

(e) of the formula (C)R_(a)—C≡C-E₂  (C)

(f) of the formulas (D1, D2 and D3)R_(a)—CH₂—CH═CH₂  (D1)R_(a)—CH═C═CH₂  (D2)R_(a)—CH₂C≡C—H  (D3)where R_(a), E₁, E₂, M are as defined above, in the presence of:

(1) a Lewis Acid,

(2) a proton acid with a pK_(a) of <about 5 or

(3) a salt of a secondary amine of the formula

with an acid of pK_(a) of <about 2. The Lewis acid both accelerates theconjugate addition and favors formation of the 7α-stereochemistry.

Adducts (-B) and (-C) are transformed into —CO—OH of carboxylic acid(VI) by treatment with one or more oxidizing agents. The oxidizingagent(s) must be capable of cleaving the C=M double bond to acarbon-oxygen double bond, cleaving the C—R_(b2) single bond to acarbon-oxygen single bond, and cleaving the carbon-carbon triple bond tocarboxylic acid. The choice of oxidizing agent(s) depends on theinherent difficulty of oxidation of the substituent —CR_(b2)=M or—C≡C—R₂. The greater the difficulty of oxidation, the stronger theoxidizing agent that will be required. Suitable oxidizing agents includeozone, singlet oxygen, triplet oxygen, hydrogen peroxide,hydroperoxides, percarboxylic acids, hypohalites, and the like. In thecase of 2-methylfuran adduct (II), transformation into carboxylic acid(VI) is preferably accomplished by treatment with potassium hypobromitefollowed by ozone followed by dimethylsulfide followed by hydrogenperoxide.

The allyl adduct (-D1) is transformed into G-OH of the carboxylic acid(VI) by double bond isomerization to —CH═CH—CH₃ followed by ozonizationwith an oxidative work-up (such as sodium chlorite). The double bondisomerization can be accomplished by any of the following reagents,rhodium trichloride in ethanol at reflux, HRuCl[P(—φ)₃]₃ at about 90°,LiNH(CH₂)₃NH₂ (lithium 1,3-diaminopropane) at 20-25°, PdCl₂(φ—CN)₂ intoluene at about 80°, HRh(CO)[P(—φ)₃]₃ at 20-250, ClRh[P(—P)₃]₃ intoluene at reflux, Cl₂Ru[P(—φ)₃]₃ at 100° and cobalt chloride/sodiumborohydride/P(—φ)₃ at about −18°.

The propargyl adduct (-D2) is transformed into the —CO—OH functionalityof the carboxylic acid (VI) by base or transition metal-catalyzedisomerization to adduct (—C) when R_(c2) is C₁ alkyl, which is cleavedby the method discussed above. Suitable bases for isomerization of (-D2)to (-C) include sodium amide in ammonia or THF, potassium3-aminopropylaminde (known as “KAPA”) in THF, potassium hydroxide inethylene glycol at about 150°, potassium t-butoxide in DMSO ort-butanol, or sodium or potassium hydride in DMF or THF. Suitabletransition metal catalysts include Yb[φ₂C═N—φ](HMPA)₄ and HCo(N₂)[P(—φ)₃]₃.

The allenyl adduct (-D3) is transformed into the —CO—OH functionality ofthe carboxylic acid (VI) by ozonization with an oxidative work-up (suchas sodium chlorite).

The present invention includes a four-step process for thetransformation of a 7α-substituted steroid (II) to the correspondingcarboxylic acid (VI) product. The four steps are (1) ring opening, (2)ozonolysis, (3) reaction with a hydroperoxy deoxygenating agent and (4)reaction with an oxidatively cleaving agent. The four-step process ofthe invention produces better yields of the carboxylic acid (VI) thanexpected based on prior art process steps. The carboxylic acid (VI) isobtained by:

(1) contacting the 7α-substituted steroid of formula (II) with an agentselected from the group consisting of:

-   -   (a) a halogenating agent in the presence of water and a base        whose conjugate acid has a pK_(a) of >about 8,    -   (b) an oxygen donating agent,    -   (c) electrochemical oxidation,    -   (d) a quinone in the presence of water or    -   (e) nonquinone oxidants; and

(2) contacting the reaction mixture of step (1) with ozone in thepresence of an alcohol of the formula R₇₋₂—OH;

(3) contacting the reaction mixture of step (2) with a hydroperoxydeoxygenating agent and

(4) contacting the reaction mixture of step (3) with anoxidatively-cleaving agent. Each of these steps was thoroughly discussedabove when the steps of the process were discussed individually. Thisprocess combines those same steps and they are practiced in the samemanner and same way as discussed above.

The present invention includes a three-step process for thetransformation of a 7α-substituted steroid (II) to the correspondingcarboxylic acid (VI) product, see EXAMPLE 34, Step (1). The three stepsare (1) ozonolysis, (2) reaction with a hydroperoxy deoxygenating agentand (3) reaction with an oxidatively cleaving agent. The three-stepprocess of the invention is a process to prepare the carboxylic acid(VI) which comprises:

(1) contacting a 7α-substituted steroid (II) with ozone in the presenceof an alcohol of the formula R₇₋₂—OH;

(2) contacting the reaction mixture of step (1) with a hydroperoxydeoxygenating agent and

(3) contacting the reaction mixture of step (2) with an oxidativelycleaving agent. Each of these steps was thoroughly discussed above whenthe steps of the process were discussed individually. This processcombines those same steps and they are practiced in the same manner andsame way as discussed above. The carboxylic acid (VI) can be readilytransformed to its tautomer-like the bislactone (VII) by contacting withan acid, see EXAMPLE 34, Step (2). In the process of the invention it isthe carboxylic acid (VI) which is transformed to the methyl ester (VIII)and ultimately to eplerenone (IX). It is possible to isolate and purifythis carboxylic acid (VI) by crystallization. However, one runs the riskthat it will isomerize to the bislactone (VII) which is morethermodynamically stable. Therefore, as a practical matter it ispreferable not to stop at the end of EXAMPLE 34, Step (1) but carry onthru the reaction mixture and isolate and crystallize the bislactone(VII). Hence, it is easier and preferable to carry the processexemplified in EXAMPLE 34 on thru Step (2), purify the bislactone (VII)obtained and then convert the bislactone (VII) back to the carboxylicacid (VI) for transformation to the methyl ester (VIII).

Eplerenone (IX) is a pharmaceutical agent useful for the treatment ofhyperaldosteronism, edema, hypertension and congestive heart failure,see U.S. Pat. No. 4,559,332.

The present invention also includes a novel process to transform11α-hydroxy steroids to the corresponding Δ⁹⁽¹¹⁾-steroids. TheΔ⁹⁽¹¹⁾-functionality is very useful in producing eplerenone (IX) becauseit is readily transformed to the corresponding 9α,11α-epoxidefunctionality of eplerenone (IX).

The 11α-hydroxy steroid (CIV) starting materials are known to thoseskilled in the art. More particularly, the 11α-hydroxy-17-lactone (CI),11α,17β-dihydroxypregn-4-en-3-one-7α,21-dicarboxylic acid, γ-lactone,methyl ester, is known, see, Drugs of the Future, 24(5), 488-501 (1999),compound (VI).

For the 11α-hydroxy steroids (CIV) it is preferred that the steroidA-ring is:

-   -   (1) W₁ is —H:—H and W₂ is —H:—H or W₁ is W₁₋₁:W₁₋₂ and W₂ is        W₂₋₁:W₂₋₂ where one of W₁₋₁ or W₁₋₂ is taken together with one        of W₂₋₁ or W₂₋₂ to form a second bond between the carbon atoms        to which they are attached and the other or W₁₋₁ or W₁₋₂ and        W₂₋₁ or W₂₋₂ is —H; W₃ is ═O, W₄₋₁ is W₄₋₁:W₄₋₂ where one of        W₄₋₁ and W₄₋₂ is taken together with W₅ to form a second bond        between the carbon atoms to which they are attached and the        other of W₄₋₁ and W₄₋₂ is —H;    -   (2) W₃ is ═O—W₄ is —H:—H and W₅ is in the α-orientation and is .        . . O—CO— (attached at C₇ to form a 5,7-lactone) and where W₁        and W₂ are as defined above;    -   (3) W₃ is —O—W₃₋₃:—O—W₃₋₄; W₄ is W₄₋₃:W₄₋₄, where one of W₄₋₃        and W₄₋₄ is taken together with W₄₋₃ to form a second bond        between the atoms to which they are attached and the other of        W₄₋₃ and W₄₋₄ is —H; W₃₋₃ and W₃₋₄ are:        -   (a) the same or different and are C₁-C₅ alkyl,        -   (b) taken together to form a cyclic moiety selected from the            group consisting of:            -   (i) —CH₂—CH₂—,            -   (ii) —CH₂—CH₂—CH₂—,            -   (iii) CH₂—C(CH₃)₂—CH₂—; and where W₁ and W₂ are as                defined above;    -   (4) W₃ is O—W₃:—O—W₃₋₄; W₄ is —H:—H; Ws forms a second bond        between C₅ and C₆; W₃₋₃ and W₃₋₄ are as defined above:    -   (5) W₃ is W₃₋₅:W₃₋₆; where        -   (a) one of W₃₋₅ and W₃₋₆ is —H and the other of W₃₋₅ and            W₃₋₆ is:            -   (i) —O—W_(3-5A) where W_(3-5A) is C₁-C₃ alkyl,            -   (ii) —O—CO—W_(3-5A) where W_(3-5A) is as defined above,            -   (iii) —N(W_(3-5A))₂ where W_(3-6A) is as defined above,            -   (iv) piperazinyl,            -   (v) morpholinyl,            -   (vi) piperidinyl,        -   (b) W₃₋₅ and W₃₋₆ are taken together with the carbon atom to            which they are attached to form a cyclic moiety including:            -   (i) —O—CH₂—CH₂—O—,            -   (ii) —O—CH₂—CH₂CH₂—O—,            -   (iii) —O—CH₂—C(CH₃)₂—CH₂—O— and where W₄ is —H:—H; W₅                forms a second bond between C₅ and C₆;    -   (6) W₃ is W₃₋₇:W₃₋₈ and where W₄ is W₄₋₇:W₄₋₈ where        -   (a) one of W₃₋₇ and W₃₋₈ is:            -   (i) —O—W_(3-7A) where W_(3-7A) is C₁-C₃ alkyl,            -   (ii) —O—CO—W_(3-7A) where W_(3-7A) is as defined above,            -   (iii) —N(W_(3-7A))₂ where W_(3-7A) is as defined above,            -   (iv) piperazinyl,            -   (v) morpholinyl,            -   (vi) piperidinyl, and where the other of W₃₋₇ and W₃₋₈                is taken together with one of W₄₋₇ and W₄₋₈ form a                second bond between the carbon atoms to which they are                attached and the other of W₄₋₇ and W₄₋₈ is —H; W₅ forms                a second bond between C₅ and C₆;    -   (7) W₃ is α-W₃₋₉:β-W₃₋₁₀; where W₃₋₉ is —H and W₃₋₁₀ is:        -   (a) —O—CO—W_(3-10A) where W_(3-10A) is C₁-C₃ alkyl,        -   (b) —O—CO—W_(3-10B) where W_(3-10B) is            -   (i) C₁-C₄ alkyl,            -   (ii) —φ optionally substituted with one thru three C₁-C₃                alkyl, —F, —Cl, —Br, —I, C₁-C₃ alkoxy,            -   (iii) —CH₂— where φ is optionally substituted with one                thru three C₁-C₃ alkyl, —F, —Cl, —Br, —I, C₁-C₃ alkoxy;                where WR₄ is —H:—H; and W₅ forms a second bond between                the carbon atoms at C₅ and C₆; and where W₁ and W₂ are                as defined above;    -   (8) W₃ is α-W₃₋₉:β-W₃₋₁₀; where W₄ is W₄₋₉:W₄₋₁₀ where W₃₋₉ and        W₃₋₁₀ are as defined above; where one of W₄₋₉ and W₄₋₁₀ taken        together with W₅ forms a second bond between the atoms to which        they are attached and the other of W₄₋₉ and W₄₋₁₀ is —H; and        where W₁ and W₂ are as defined above.

It is more preferred that the steroid A-ring functionality be:

(1) W₁ is —H:—H and W₂ is —H:—H or W₁ is W₁₋₁:W₁₋₂ and W₂ is W₂₋₁:W₂₋₂where one of W₁₋₁ or W₁₋₂ is taken together with one of W₂₋₁ or W₂₋₂ toform a second bond between the carbon atoms to which they are attachedand the other or W₁₋₁ or W₁₋₂ and W₂₋₁ or W₂₋₂ is —H; W₃ is ═O, W₄ isW₄₋₁:W₄₋₂ where one of W₄₋₁ and W₄₋₂ is taken together with W₅ to form asecond bond between the carbon atoms to which they are attached and theother of W₄₋₁ and W₄₋₂ is —H;

(7) W₃ is α-W₃₋₉:β-W₃₋₁₀; where W₃₋₉ is —H and W₃₋₁₀ is:

-   -   (b) —CO—W_(3-10A) where W_(3-10A) is C₁-C₃ alkyl,    -   (c) —CO—O—W_(3-10A) where W_(3-10B) is        -   (i) C₁-C₄ alkyl,        -   (ii) —φ optionally substituted with one thru three C₁-C₃            alkyl, —F, —Cl, —Br, —I, C₁₁-3 alkoxy,        -   (iii) —CH₂—φ where φ is optionally substituted with one thru            three C₁-C₃ alkyl, —F, —Cl, —Br, —I, C₁-C₃ alkoxy; where WR₄            is —H:—H; and W₅ forms a second bond between the carbon            atoms at C₅ and C₆; and where W₁ and W₂ are as defined            above.

It is even more preferred that the steroid A-ring functionality be:

-   -   (1) W₁ is —H:—H and W₂ is —H:—H or W₁ is W₁₋₁:W₁₋₂ and W₂ is        W₂₋₁:W₂₋₂ where one of W₁₋₁ or W₁₋₂ is taken together with one        of W₂₋₁ or W₂₋₂ to form a second bond between the carbon atoms        to which they are attached and the other or W₁₋₁ or W₁₋₂ and        W₂₋₁ or W₂₋₂ is —H; W₃ is ═O, W₄ is W₄₋₁:W₄₋₂ where one of W₄₋₁        and W₄₋₂ is taken together with W₅ to form a second bond between        the carbon atoms to which they are attached and the other of        W₄₋₁ and W₄₋₂ is —H;

For the 11α-hydroxy steroids (CIV), it is preferred that the steroidD-ring is:

where W₁₇ is:

-   -   (1) ═O,    -   (2) α-W₁₇:β-W₁₇₋₂ where:        -   (a) W₁₇₋₁ and W_(17.2) are taken together with the attached            carbon atom to form an epoxide of the formula . . . CH₂—O—,        -   (b) W₁₇₋₁ and W₁₇₋₂ are taken together with the attached            carbon atom to form a lactone of the formula . . .            CH₂—CH₂—CO—O—;    -   (3) α-W₁₇₋₃:β-W₁₇₋₄ where        -   (a) W_(17.3) is:            -   (i) —H,            -   (ii) —O—CO—W_(17-3A) where W_(17-3A) is —H or —CO—W₁₇₋₃₈                where W₁₇₋₃₈ is C₁-C₄ alkyl or —φ and        -   (b) W₁₇₋₄ is —CO—CH₃;    -   (4) α-W₁₇₋₅:β-W₁₇₋₆ where        -   (a) W₁₇₋₅ is:            -   (i) —O—CO—W_(17-4A) where W_(17-5A) is C₁-C₄ alkyl or                —φ,        -   (b) W₁₇₋₆ is:            -   (i) —CO—CH₂—O—W_(17-6A) where W_(17-6A) is C₁-C₄ alkyl                or

For the eplerenone-type compounds, it is preferred that W₁₇ is:

-   -   (1) ═O,    -   (2) α-W₁₇₋₁:β-W₁₇₋₂ where:        -   (a) W₁₇₋₁ and W₁₇₋₂ are taken together with the attached            carbon atom to form an epoxide of the formula . . . CH₂—O—,        -   (b) W₁₇₋₁ and W₁₇₋₂ are taken together with the attached            carbon atom to form a lactone of the formula . . .            CH₂—CH₂—CO—O—.

It is more preferred that for the eplerenone-type compounds that W₁₇ is:

-   -   (1) ═O,    -   (2) α-W₁₇₋₁:β-W₁₇₋₂ where:        -   (b) W₁₇₋₁ and W₁₇₋₂ are taken together with the attached            carbon atom to form a lactone of the formula . . .            CH₂—CH₂—CO—O—.

For the progesterones and hydroxyprotesterones it is preferred that thatW₁₇ is:

-   -   (3) α-W₁₇₋₃:β-W₁₇₋₄ where        -   (a) W₁₇₋₃ is:            -   (i) —H,            -   (ii) —O—CO—W_(17-3A) where W_(17-3A) is —H or CO—W₁₇₋₃₈                where W_(17-3B) is C₁-C₄ alkyl or —φ and        -   (b) W₁₇₋₄ is CO—CH₃.

For the corticoids it is preferred that W₁₇ is:

-   -   (4) α-W₁₇₋₅:β-W₁₇₋₆ where        -   (a) W₁₇₋₅ is:            -   (i) —O—CO—W_(17-5A) where W_(17-5A) is C₁-C₄ alkyl or                —φ,        -   (b) W₁₇₋₄ is:            -   (i) —CO—CH—O—W_(17-6A) where W_(17-6A) is C₁-C₄ alkyl or                —φ.

The preferred combinations of steroid A-, B- and D-rings, especially forthe eplerenone-type compounds, includes the ring systems set forth inCHART C. The 11α-hydroxy steroids (CIV) of CHART C are known to thoseskilled in the art or can be readily prepared by known methods fromknown compounds.

In the process of the present invention the 11α-hydroxy-17-lactones (CI)or 11α-hydroxy steroids (CIV) starting material is contacted with aN-fluoroalkylamine reagent of the formula (CVI).

where:

Z₁ is C₁-C₄ alkyl;

Z₂ is C₁-C₄ alkyl and where Z₁ and Z₂ together with the attachednitrogen atom form a 5- or 6-member heterocycle selected from the groupconsisting of pyrrolidinyl, piperazinyl, piperidinyl and morpholinyl;

Z₃ is —F or —F₃. It is preferred that Z₁ and Z₂ are C₁-C₃ alkyl. It ismore preferred that Z₁ and Z₂ are C₁ alkyl or C₂ alkyl. It is preferredthat the N-fluoroalkylamine (CVI) isN-(1,1,2,3,3,3-hexafluoropropyl)diethylamine, which is known as Ishikawareagent, or 1,1,2,2-tetrafluoroethyl-N,N-dimethylamine.

The process of the invention is preferably performed by use of about 1equivalent of 11α-hydroxy-17-lactone (CI) or 11α-hydroxy steroid (CIV)and from about 1 to about 1.5 equivalents of Ishikawa reagent; morepreferred is about 1,2 equivalents of Ishikawa reagent. It is preferableto perform the process of the invention in a temperature range of fromabout 20 to about 82°; more preferably from about 40 to about 70°. Thereaction usually takes from about 1 hr to about 24 to complete dependingon reaction conditions especially temperature and concentration. Forexample at about 60° and 0.8 molar, the reaction takes about 3 hours.

The 11α-hydroxy-17-lactone (CI) or 11α-hydroxy steroid (CIV) can beadded to the N-fluoroalkylamine reagent (CVI) or the N-fluoroalkylaminereagent (CVI) can be added to the 11α-hydroxy-17-lactone (CI) or11α-hydroxy steroid (CIV); it is more practical to add theN-fluoroalkylamine reagent (CVI) to the 11α-hydroxy-17-lactone (CI) or11α-hydroxy steroid (CIV).

It is preferred to perform the process of the present invention in asolvent that is dry (KF is <0.5%), such as acetonitrile.

The Δ⁹⁽¹¹⁾-17-lactone of formula (CII),17β-hydroxypregna-4,9(11)-dien-3-one-7α,21-dicarboxylic acid, γ-lactone,methyl ester, is known, see U.S. Pat. No. 4,559,332, Example 1(d) andinternational Publication WO98/25948, page 284. It is useful in thepreparation of a pharmaceutical agent,9α,11α-epoxy-17β-hydroxypregn-4-en-3-one-7α,21-dicarboxylic acid,γ-lactone, methyl ester, known as eplerenone (CIII).

The steroid C-ring functionality Δ⁹⁽¹¹⁾- of compounds (CII) and (CV) isa very useful functionality to chemists skilled in the art of steroids.It can be readily transformed to the corresponding 9α,11α-epoxyfunctionality and the 9α-fluoro-11β-hydroxy functionality as well as11-keto and others as is well known to those skilled in the art. Thesecompounds are useful pharmaceutical agents. Hence, the process of theinvention as it pertains to the transformation of the 11α-hydroxysteroid (CIV) to the corresponding Δ⁹⁽¹¹⁾ steroid (CV) is a very usefulprocess and is operable with a wide variety of 11α-hydroxy steroids(CIV) as is apparent to those skilled in the art. This includesprogesterones, 17α-hydroxyprogesterones, corticoids as well as the usualcommon derivatives and analogs thereof such as esters, etc. Therefore,the process produces Δ⁹⁽¹¹⁾-steroids (CV) which are useful intermediatesin the preparation of pharmaceutically useful steroids. One skilled inthe art with a given Δ⁹⁽¹¹⁾-steroid (CV) would know how to transform itto a pharmaceutically useful product.

The present invention also includes a number of processes fortransforming 11α-hydroxy compounds to the corresponding Δ⁹⁽¹¹⁾-compoundsby one or more processes described above. For example, described areprocesses for the transformation of (1) a 11α-hydroxy-7α-substitutedsteroid (II) to the corresponding Δ⁹⁽¹¹⁾-7α-substituted steroid (II),(2) a process for transforming a 11α-hydroxy cis enedione (III-cis) or11α-hydroxy trans enedione (III-trans) to the corresponding Δ⁹⁽¹¹⁾-transenedione (III-trans) and (3) for transforming a 11α-hydroxy-hydroxycompound (IV-OH) or a 11α-hydroxy-hydroperoxy compound (IV-OOH) or a11α-hydroxy biscarbonyl compound (V) or mixture thereof to thecorresponding Δ⁹⁽¹¹⁾-carboxylic acid (VI).

Definitions and Conventions

The definitions and explanations below are for the terms as usedthroughout this entire document including both the specification and theclaims.

I. Conventions for Formulas and Definitions of Variables

The chemical formulas representing various compounds or molecularfragments in the specification and claims may contain-variablesubstituents in addition to expressly defined structural features. Thesevariable substituents are identified by a letter or a letter followed bya numerical subscript, for example, “Z₁” or “R₁” where “i” is aninteger. These variable substituents are either monovalent or bivalent,that is, they represent a group attached to the formula by one or twochemical bonds. For example, a group Z₁ would represent a bivalentvariable if attached to the formula CH₃—C(=Z₁)H. Groups R_(i) and R_(j)would represent monovalent variable substituents if attached to theformula CH₃—CH₂—C(R_(i))(R_(j))H₂. When chemical formulas are drawn in alinear fashion, such as those above, variable substituents contained inparentheses are bonded to the atom immediately to the left of thevariable substituent enclosed in parenthesis. When two or moreconsecutive variable substituents are enclosed in parentheses, each ofthe consecutive variable substituents is bonded to the immediatelypreceding atom to the left which is not enclosed in parentheses. Thus,in the formula above, both R_(i) and R_(j) are bonded to the precedingcarbon atom. Also, for any molecule with an established system of carbonatom numbering, such as steroids, these carbon atoms are designated asC_(i), where “i” is the integer corresponding to the carbon atom number.For example, C₆ represents the 6 position or carbon atom number in thesteroid nucleus as traditionally designated by those skilled in the artof steroid chemistry. Likewise the term “R₆” represents a variablesubstituent (either monovalent or bivalent) at the C₆ position.

Chemical formulas or portions thereof drawn in a linear fashionrepresent atoms in a linear chain. The symbol “—” in general representsa bond between two atoms in the chain. Thus CH₃—0—CH₂—CH(R_(i))—CH₃represents a 2-substituted-1-methoxypropane compound. In a similarfashion, the symbol “═” represents a double bond, e.g.,CH₂═C(R_(i))—O—CH₃, and the symbol “≡” represents a triple bond, e.g.,HC≡C—CH(R_(i))—CH₂—CH₃. Carbonyl groups are represented in either one oftwo ways: —CO— or —C(═O)—, with the former being preferred forsimplicity.

Chemical formulas of cyclic (ring) compounds or molecular fragments canbe represented in a linear fashion. Thus, the compound4-chloro-2-methylpyridine can be represented in linear fashion byN*═C(CH₃)—CH═CCl—CH═C*H with the convention that the atoms marked withan asterisk (*) are bonded to each other resulting in the formation of aring. Likewise, the cyclic molecular fragment, 4-(ethyl)-1-piperazinylcan be represented by —N*—(CH₂)₂—N(C₂H₅)—CH₂—C*H₂.

A rigid cyclic (ring) structure for any compounds herein defines anorientation with respect to the plane of the ring for substituentsattached to each carbon atom of the rigid cyclic compound. For saturatedcompounds which have two substituents attached to a carbon atom which ispart of a cyclic system, —C(X₁)(X₂)— the two substituents may be ineither an axial or equatorial position relative to the ring and maychange between axial/equatorial. However, the position of the twosubstituents relative to the ring and each other remains fixed. Whileeither substituent at times may lie in the plane of the ring(equatorial) rather than above or below the plane (axial), onesubstituent is always above the other. In chemical structural formulasdepicting such compounds, a substituent (X₁) which is “below” anothersubstituent (X₂) will be identified as being in the alpha (α)configuration and is identified by a broken, dashed or dotted lineattachment to the carbon atom, i.e., by the symbol “ - - - ” or “ . . .”. The corresponding substituent attached “above” (X₂) the other (X₁) isidentified as, being in the beta (B) configuration and is indicated byan unbroken line attachment to the carbon atom.

When a variable substituent is bivalent, the valences may be takentogether or separately or both in the definition of the variable. Forexample, a variable RA attached to a carbon atom as —C(═R₁)— might bebivalent and be defined as oxo or keto (thus forming a carbonyl group—C(—R_(i))— or as two separately attached monovalent variablesubstituents α-R_(i-j) and β-R_(j-k). When a bivalent variable, R_(i),is defined to consist of two monovalent variable substituents, theconvention used to define the bivalent variable is of the form“α-R_(i-j):β-R_(i-k)” or some variant thereof. In such a case bothα-R_(i-j) and β-R_(i-k) are attached to the carbon atom to give—C(α-R_(i-j))(β-R_(i-k))—. For example, when the bivalent variable R₆,—C(═R₆)— is defined to consist of two monovalent variable substituents,the two monovalent variable substituents are α-R₆₋₁:β-R₆₋₂, . . .α-R₆₋₉:β-R₆₋₁₀, etc, giving —C(α-R₆₋₁)(β-R₆₋₂)— . . .—C(α-R₆₋₉)(β-R₆₋₁₀)—, etc. Likewise, for the bivalent variable R₁₁,—C(═R₁₁)—, two monovalent variable substituents are α-R₁₁₋₁:β-R₁₁₋₂. Fora ring substituent for which separate α and β orientations do not exist(e.g. due to the presence of a carbon carbon double bond in the ring),and for a substituent bonded to a carbon atom which is not part of aring the above convention is still used, but the α and β designationsare omitted.

Just as a bivalent variable may be defined as two separate monovalentvariable substituents, two separate monovalent variable substituents maybe defined to be taken together to form a bivalent variable For example,in the formula —C₁(R_(i))H—C₂(R_(j))H— (C₁ and C₂ define arbitrarily afirst and second carbon atom, respectively) R_(i) and R_(j) may bedefined to be taken together to form (1) a second bond between C₁ and C₂or (2) a bivalent group such as oxa (—O—) and the formula therebydescribes an epoxide. When R_(i) and R_(j) are taken together to form amore complex entity, such as the group —X—Y—, then the orientation ofthe entity is such that C₁ in the above formula is bonded to X and C₂ isbonded to Y. Thus, by convention the designation “ . . . R_(i) and R_(j)are taken together to form —CH₂—CH₂—O—CO— . . . ” means a lactone inwhich the carbonyl is bonded to C₂. However, when designated “ . . .R_(j) and R_(i) are taken together to form —CO—O—CH₂—CH₂-the conventionmeans a lactone in which the carbonyl is bonded to C₁.

The carbon atom content of variable substituents is indicated in one oftwo ways. The first method uses a prefix to the entire name of thevariable such as “C₁-C₄”, where both “1” and “4” are integersrepresenting the minimum and maximum number of carbon atoms in thevariable. The prefix is separated from the variable by a space. Forexample, “C₁-C₄ alkyl” represents alkyl of 1 through 4 carbon atoms,(including isomeric forms thereof unless an express indication to thecontrary is given). Whenever this single prefix is given, the prefixindicates the entire carbon atom content of the variable being defined.Thus C₂₋₄ alkoxy-carbonyl describes a group CH₃—(CH₂)_(n)-0-CO— where nis zero, one or two. By the second method the carbon atom content ofonly each portion of the definition is indicated separately by enclosingthe “C_(i)-C_(j)” designation in parentheses and placing it immediately(no intervening space) before the portion of the definition beingdefined. By this optional convention (C₁-C₃)alkoxycarbonyl has the samemeaning as C₂-C₄ alkoxycarbonyl because the “C₁-C₃” refers only to thecarbon atom content of the alkoxy group. Similarly while both C₂-C₆alkoxyalkyl and (C₁-C₃)alkoxy(C₁-C₃)alkyl define alkoxyalkyl groupscontaining from 2 to 6&carbon atoms, the two definitions differ sincethe former definition allows either the alkoxy or alkyl portion alone tocontain 4 or 5 carbon atoms while the latter definition limits either ofthese groups to 3 carbon atoms.

When the claims contain a fairly complex (cyclic) substituent, at theend Of the phrase naming/designating that particular substituent will bea notation in (parentheses) which will correspond to the samename/designation in one of the CHARTS which will also set forth thechemical structural formula of that particular substituent.

II. Definitions

All temperatures are in degrees Celsius.

TLC refers to thin-layer chromatography.

LC refers to liquid chromatography.

ESTDLC refers to external standard liquid chromatography.

THF refers to tetrahydrofuran.

DMAP refers to p-dimethylaminopyridine.

DDQ refers to 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

DBU refers to 1,8-diazabicyclo[5.4.0]undec-7-ene.

DBN refers to 1,5-diazabicyclo[4.3.0]non-5-ene.

DABCO refers 1,4-diazabicyclo[2.2.2]octane.

Chromatography (column and flash chromatography) refers topurification/separation of compounds expressed as (support, eluent). Itis understood that the appropriate fractions are pooled and concentratedto give the desired compound(s).

Carboxylic acid (VI) refers to and includes the pharmaceuticallyacceptable-salts thereof.

CMR refers to C-13 magnetic resonance spectroscopy, chemical shifts arereported in ppm (δ) downfield from TMS.

NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemicalshifts are reported in ppm (d) downfield from TMS.

In the present invention the terms conversion/transformation orconvert/transform are used interchangeable and mean the same thing, thereaction of one compound to form a different compound by the processdescribed.

TMS refers to trimethylsilyl.

Oxone refers to KHSO₅.

—φ refers to phenyl (C₆H₅).

MS refers to mass spectrometry expressed as m/e, m/z or mass/chargeunit. [M+H]⁺ refers to the positive ion of a parent plus a hydrogenatom. E₁ refers to electron impact. Cl refers to chemical ionization.FAB refers to fast atom bombardment.

Pharmaceutically acceptable refers to those properties and/or substanceswhich are acceptable to the patient from a pharmacological/toxicologicalpoint of view and to the manufacturing pharmaceutical chemist from aphysical/chemical point of view regarding composition, formulation,stability, patient acceptance and bioavailability.

When solvent pairs are used, the ratios of solvents used arevolume/volume (v/v).

When the solubility of a solid in a solvent is used the ratio of thesolid to the solvent is weight/volume (wt/v).

Δ⁹-Canrenone refers to 17β-hydroxypregna-4,6,9-trien-3-one-21-carboxylicacid, γ-lactone.

Eplerenone refers to9α,11α-epoxy-17β-hydroxypregn-4-en-3-one-7α,21-dicarboxylic acid,γ-lactone, methyl ester.

Neopentylglycol refers to HO—CH₂—C(CH₃)₂—CH₂OH.

Iodosobenzene refers to φI═O.

Iodobenzenebistrifluoroacetate refers to φI(O—CO—CF₃)₂.

Iodobenzenediacetate refers to φI(O—CO—CH₃)₂.

Tritylfluoroborate is also known as triphenylcarbenium fluoroborate andrefers to φ₃C⁺BF₄ ⁻.

acac refers to acetylacetonate.

dppb refers to diphenylphosphino butane.

Tf refers to trifluoromethanesulfonate.

Dimethylsulfide refers to CH₃SCH₃.

Ishikawa reagent refers toN-(1,1,2,2,3,3,3)hexafluoropropyldiethylamine.

An “oxidatively cleaving agent” is a reagent that oxidizes thebiscarbonyl compound (V) or hydroxy compound (IV-OH) to the carboxylicacid (VI).

A “hydroperoxy-deoxygenating agent” is a reagent that removes an oxygenatom from a hydroperoxide compound (IV-OOH) to give the correspondinghydroxy compound (IV-OH).

A “deoxygenating agent” is a reagent that removes one oxygen atom from amolecule. The “hydroperoxy-deoxygenating agent” is thus a particulartype of deoxygenating agent.

A “carboxylic acid forming agent” is a reagent that induces ahydroperoxide compound (IV-OOH) to rearrange to a carboxylic acid (VI).

An “oxygen donating agent” is a reagent that provides an oxygen atom toa 7α-substituted steroid (II) to transform it into a cis enedione(III-cis).

EXAMPLES

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, practice the present invention toits fullest extent. The following detailed examples describe how toprepare the various compounds and/or perform the various processes ofthe invention and are to be construed as merely illustrative, and notlimitations of the preceding disclosure in any way whatsoever. Thoseskilled in the art will promptly recognize appropriate variations fromthe procedures both as to reactants and as to reaction conditions andtechniques.

Example 1 17β-Hydroxypregna-4,6,9(11)-trien-3-one-21-carboxylic acid,γ-lactone, cyclic 3-(2′,2′-dimethyl-1′,3′-propanediyl ketal) (I-P)

17β-hydroxypregna-4,6,9(11)-trien-3-one-21-carboxylic acid, γ-lactone3-methyl enol ether (I, 3.00 g, 8.4629 mmoles) and lithium perchlorate(199.6 mg, 1.87-61 mmoles, 0.22 equivalents) are slurried inacetonitrile (20 ml) and methylene chloride (10) are cooled to −15′,treated with 2,2-dimethyl-1,3-propyleneglycol (2.19 g, 21.027 mmoles,2.48 equivalents), then treated drop wise over 73 min. with a solutionof DDQ (2.29 g, 10.088 mmoles, 1.19 equivalents) in ethyl acetate. Afterstirring for 40 min, the reaction mixture is quenched with ammoniumhydroxide (28%, 5 ml), diluted with ethyl acetate, concentrated, dilutedwith methylene chloride, and filtered. The filtrate is diluted withethyl acetate, washed with aqueous sodium bicarbonate/sodium chloridefollowed by water, then filtered through magnesol, eluting withmethylene chloride. The eluate is concentrated to give solids which aretriturated with toluene, dried by a stream of nitrogen to give the titlecompound, CMR (CDCl₃) 14.44, 22.53, 22.78, 23.02, 24.89, 28.85, 29.22,30.07, 30.18, 31.31, 32.92, 35.37, 38.56, 39.03, 44.35, 44.43, 70.54,70.65, 95.17, 95.43, 116.80, 120.23, 127.82, 130.27, 141.83, 145.08 and176.61 δ; NMR (CDCl₃) 0.95, 0.97, 1.03, 1.18, 1.3-2.8, 3.5-3.7, 5.44,5.71, 5.80 and 6.02 δ.

Example 2 17β-Hydroxypregna-4,6,9(11)-trien-3-one-21-carboxylic acid,γ-lactone, cyclic 3-ethanediyl ketal (I-P)

17β-hydroxypregna-4,6,9(11)-trien-3-one-21-carboxylic acid, γ-lactone3-methyl enol ether (I, 300 mg, 0.8463 mmoles) in methylene chloride (5ml) is cooled to −15° then treated with ethylene glycol (220 mg, 3.544mmoles; 4.19 equivalents). To this mixture is added drop wise over 30min. a solution of DDQ (230 mg, 1.0132 mmoles, 1.20 equivalents). Afterthe addition is complete, the reaction is stirred at −15° for 5 min., atwhich time TLC analysis (ethyl acetate/cyclohexane, 66/34) showsconversion of the startling methyl enol ether (R_(f)=0.69) into thecorresponding ethylene ketal (R_(f)=0.54) was nearly complete. Thereaction is then quenched with concentrated ammonium hydroxide (0.5 ml),and filtered. The filtrate is then filtered through 1.0 g cartridgegrade magnesol and concentrated to give the title compound, bycomparison with an authentic sample, CMR (CDCl₃) 14.37, 22.95, 24.54,29.15, 30.28, 31.23, 32.87, 35.30, 38.17, 38.45, 44.27, 44.37, 64.15,64.70, 95.07, 105.94, 116.85, 122.39, 127.41, 130.24, 141.71, 145.76 and176.51 δ; NMR (CDCl₃) 0.97, 1.18, 1.3-2.9, 3.8-4.1, 5.29, 5.45, 5.70 and5.99 δ.

Example 317β-Hydroxy-7α-(5′-methyl-2′-furyl)-pregna-4,9(11)-dien-3-one-21-carboxylicacid, γ-lactone (II)

Δ⁹-canrenone (I, 90.0 g, 0.2659 moles) is mixed with nitromethane(730-735 ml). Then 2-methylfuran (49.5 ml, 45.04 g, 0.5487 moles, 2.06equivalents) is added. The resulting mixture is cooled to −20° thentreated with absolute ethanol (158 ml, 12.55 g, 0.2723 moles, 1.02equivalents) followed by boron trifluoride etherate, (d=1.1-20; 37.2 ml,41.66 g, 0.2936 moles, 1.10 equivalents). The mixture is recooled to−18.4° and stirred for 17 hrs., at which time the reaction was completeby LC. The reaction mixture is quenched with ammonia (15% aqueous, 225ml). The mixture is warmed to above 0°, water (200 ml) is added, theorganic phase is separated, and the aqueous phase is extracted withmethylene chloride 2×200 ml). The organic extracts are dried overmagnesium sulfate (100 g) then filtered through magnesol (100 gcartridge grade), washing the cake with methylene chloride (5×200 ml).The eluate is then concentrated under reduced pressure to a foam,slurried with ethyl acetate (200 ml) and reconcentrated, then dissolvedin ethyl acetate (950 ml) at 500 to 600. The mixture is concentrated toabout 500 ml volume, then diluted with cyclohexane 250 ml). The productbegins to crystallize slowly. The slurry is reconcentrated to about 500ml volume, cooled to 20-25°, further concentrated to about 400 mlvolume, then cooled to 0°. After overnight at 0°, the slurry is filteredand the cake washed with cyclohexane followed by heptane and dried in avacuum oven at 500 to give the title compound, TLC=0.37 (ethylacetate/cyclohexane, 66/34), CMR (CDCl₃) 13.38, 14.12, 23.18, 26.83,29.14, 31.26, 32.93, 33.93, 34.18, 35.39, 37.57, 38.52, 40.78, 41.90,42.39, 44.08, 95.19, 105.89, 107.12, 119.73, 126.24, 149.99, 152.74,167.45, 76.53 and 198.56; NMR (CDCl₃) 0.95, 1.43, 1.4-2.6, 2.16, 2.93,3.30, 5.68 and 5.74 δ.

The filtrate is concentrated to a foam which is dissolved in ethylacetate (40 ml), concentrated to about 20 ml, seeded, diluted withcyclohexane (20 ml), concentrated to about 30 ml, cooled to 0° over theweekend, then filtered, washed with ethyl acetate/cyclohexane (½) anddried to give additional title compound.

Example 417β-Hydroxy-7α-(trans-1′,4′-dioxopent-2′-en-1′-yl)pregna-4,9(11)-dien-3-one-21-carboxylicacid, γ-lactone (III-trans)

Step A:17β-Hydroxy-7α-(cis-1′,4′-dioxopent-2′-en-1′-yl)pregna-4,9(11)-dien-3-one-21-carboxylicacid, γ-lactone (III-cis)

A mixture of17β-hydroxy-7α-(5′-methyl-2′-furyl)-pregna-4,9(11)-dien-3-one-21-carboxylicacid, γ-lactone (II, EXAMPLE 3, 5.04 g, 11.9843 mmoles) and potassiumacetate (1.7 g, 17.32 mmoles, 1.45 equivalents) in THF (40 ml) and water(12.5 ml) at 23.8° is treated with dibromantin (2.0 g, 6.995 mmoles,0.58 equivalents) followed by isobutyl vinyl ether (500 μl, 384 mg,3.834 mmoles, 0.32 equivalents). The reaction mixture is stirred at20-25° for 1 hr., at which time conversion of the starting material(II), R_(f)=0.50) into cis- and trans-enedione (R_(f)=0.11) is completeby TLC (ethyl acetate/cyclohexane, 66/34). The reaction mixture isdiluted with water (200 ml) and extracted with methylene chloride (2×100ml). The extracts are combined, washed with water (50 ml), dried overmagnesium sulfate, filtered and concentrated to give the cis-enedione(III-cis).

Step B:17β-Hydroxy-7α-(trans-1′,4′-dioxopent-2′-en-1′-yl)pregna-4,9(11)-dien-3-one-21-carboxylicacid, γ-lactone (III-trans)

The concentrate (Step A) is taken up in chloroform (100 ml) and themixture is stirred at 20-25° for 20 hrs., at which time conversion ofcis-enedione into trans-enedione is judged to be complete as measured byTLC and LC (cis/trans=1.1/98.9). The mixture is then concentrated andthe concentrate is taken up in ethyl acetate (20 ml) at 20-25° anddiluted with cyclohexane (80 ml), which induces crystallization. Theslurry is cooled, filtered, and the cake washed with cyclohexane anddried under reduced pressure at 50° to give the title compound, CMR(CDCl₃) 13.98, 23.28, 27.08, 28.66, 29.01, 31.26, 32.77, 33.61, 34.01,35.22, 35.28, 40.48, 40.51, 42.41, 44.43, 48.13, 94.77, 118.81, 126.03,135.89, 137.04, 142.16, 165.21, 176.32, 197.81, 198.26 and 200.18; NMR(CDCl₃) 1.04, 1.30, 1.51, 1.5-3.6, 2.45, 5.71, 5.78 and 6.89 δ; MS(electrospray) m/e=435 (p⁺−1) negative ion mode;

Example 5 17β-Hydroxypregna-4,9(11)-dien-3-one-7α,21-dicarboxylic acid,γ-lactone (VI)

Step A:17β-hydroxy-7α-(1′-oxo-2′-isopropoxy-2′-hydroxy-ethyl)pregna-4,9(11)-dien-3-one-21-carboxylicacid, γ-lactone (IV-OH);17β-hydroxy-7α-(1′-oxo-2′-isopropoxy-2′-hydrohydroperoxyethyl)pregna-4,9(11)-dien-3-one-21-carboxylicacid, γ-lactone (IV-COH) and17β-hydroxy-7α-(2′-oxo-acetyl)-pregna-4,9(11)-dien-3-one-21-carboxylicacid, γ-lactone (V)

A mixture of17β-hydroxy-7α-(trans-1′,4′-dioxo-pent-2′-en-1′-yl)pregna-4,9(11)-dien-3-one-21-carboxylicacid, γ-lactone (III-trans, EXAMPLE 4, 551.8 mg, 1.2640 mmoles) inisopropanol (11 ml) and methylene chloride (5 ml) is cooled to −55°.Ozone in oxygen is bubbled through this mixture until 0.4 area % (by LC)trans-enedione (III) remained. The mixture is purged of ozone bysparging with nitrogen for 7 minutes to give a mixture of the titlecompounds.

Step B:17β-hydroxy-7α-(1′-oxo-2′-isopropoxy-2′-hydroxy-ethyl)pregna-4,9(11)-dien-3-one-21-carboxylicacid, γ-lactone (IV-OH),17β-hydroxy-7α-(1′,2′-dioxo-ethyl)pregna-4,9(11)-dien-3-one-21-carboxylicacid, γ-lactone (V) and17β-Hydroxy-7α-(2′-oxo-acetyl)-pregna-4,9(11)-dien-3-one-21-carboxylicacid, γ-lactone (V)

The mixture of Step A is then quenched with dimethylsulfide (340 μl, 288mg, 4.630 mmoles, 3.66 equivalents), warmed to 20-25° stirred at 20-25°for 50 min. to give a mixture of the title compounds.

Step C: 17β-Hydroxypregna-4,9(11)-dien-3-one-7α,21-dicarboxylic acid,γ-lactone (VI)

The mixture of Step B is then treated with hydrogen peroxide (70%aqueous, 430 μl, 560 mg, containing 392 mg (11.52 mmoles, 9.12equivalents) of hydrogen peroxide) and a solution of potassiumbicarbonate (637.7 mg, 6.369 mmoles, 5.04 equivalents) in water (8 ml).The resulting two-phase mixture is diluted with enough methanol toproduce a one-phase mixture (5 ml), which is then stirred at 20-25° for16 hrs., then diluted to a volume of 500 ml with methanol for purpose ofLC analysis. LC analysis indicates the title compound is obtained bycomparison with a known compound.

A 20.0 ml portion of the 500 ml solution was withdrawn and furtherdiluted with methanol to a volume of 50 ml. This solution (containing17.3 mg [0.0450 moles] carboxylic acid by LC) is concentrated to a lowvolume, diluted with water, acidified with hydrochloric acid (1N), andextracted with methylene chloride (2×). The two extracts are each washedin sequence with water, then combined and concentrated. The concentrateis taken up in methanol/toluene (1/1; 2 ml) and treated with a mixtureof trimethylsilyldiazomethane, (CH₃)₃SiCHN₂, in hexane (2.0 M, 0.25 ml,0:50 mmoles, 11.1 equivalents). TLC analysis (ethyl acetate/cyclohexane;66/34) indicates the title compound is obtained, R_(f)=0.23; LC analysis(210 nm detection) indicates the same retention time as a known standardand that the title compound is obtained.

Example 6 17β-Hydroxypregna-4,9(11)-dien-3-one-7α,21-dicarboxylic acid,γ-lactone, methyl ester (VIII)

The remainder of the 500 ml mixture of Step C of EXAMPLE 5 (479 ml,containing 414.4 mg [1.0777 mmoles] 17β-hydroxypregna-4,9(11)-dien-3-one7α,21-dicarboxylic acid, γ-lactone (VI, EXAMPLE 5C) is concentratedpartially, diluted with water (20 ml), concentrated to a volume of about20 ml, treated with hydrochloric acid (18 ml) and extracted withmethylene chloride (25 ml, then 2×15 ml). The extracts are washed withwater (30 ml), combined, and concentrated to a volume of 50.0 ml. Halfof this mixture is concentrated to a low volume, diluted with ethylacetate, and extracted with potassium bicarbonate (25% aqueous, 20 ml,then 10 ml). The extracts are combined, acidified to pH 3 withhydrochloric acid (1 N) and extracted with methylene chloride (40 ml,then 2×15 ml). The extracts are then combined, washed with water,concentrated to a volume of <1 ml, and treated with a solution of sodiumcarbonate (349.6 mg, 3.298 mmoles, 6.12 equivalents based on carboxylicacid) in water (1.0 ml) followed by tetra-n-butylammonium bisulfate,(n-butyl)₄NHSO₄, (20.4 mg, 0.0601 mmoles, 0.11 equivalents) followed bydimethylsulfate (108 μl, 144.0 mg, 1.14 mmoles, 2.11 equivalents). Themixture is diluted with methylene chloride (0.1 ml), stirred at 20-25°for 11.5 hrs., treated with hydrochloric acid (1 N, 10 ml) and extractedwith methylene chloride (10 ml, then 2×5 ml). The extracts are combined,washed with water, and concentrated to give the title compound,consistent with a known standard.

Example 717β-Hydroxy-7α-(cis-3′-acetoxyacryloyl)-pregna-4,9(1)-dien-3-one-21-carboxylicacid, γ-lactone (X-cis)

A stream of O₃/O₂ (ozone/oxygen) is passed through a cold 1-(—78°)mixture of17β-hydroxy-7α-(5′-methyl-2′-furyl)-pregna-4,9(11)-dien-3-one-21-carboxylicacid, γ-lactone (II, EXAMPLE 3, 3.0138 g, 7.1663 mmoles) in methylenechloride (40 ml) and methanol (10 ml) until the starting material hadbeen consumed (LC, 25 min), then the mixture is purged with O₂ followedby nitrogen, quenched with trimethylphosphite (3.0 ml, 3.16 g, 25.435mmoles, 3.55 equivalents), and warmed to 20-25°. After stirring for 1hr., LC analysis indicates the title compound is obtained, CMR (100 MHz,CDCl₃) 198.49, 198.23, 176.43, 166.63, 166.10, 142.74, 142.44, 125.87,118.12, 110.39, 94.99, 49.30, 44.47, 42.30, 40.59, ˜40, 35.46, 35.33,34.11, 33.63, 32.83, 31.37, 29.11, 27.26, 23.31, 20.67 and 14.06 δ; NMR(400 MHz, CDCl₃) 0.94, 1.40, 1.5-2.9, 2.29, 5.38, 5.63 and 7.48 δ.

Example 817β-Hydroxy-7α-(trans-3′-acetoxyacryloyl)-pregna-4,9(11)-dien-3-one-21-carboxylicacid, γ-lactone (X-trans)

After stirring the reaction mixture of EXAMPLE7β-hydroxy-7α-(cis-3′-acetoxyacryloyl)-pregna-4,9(11)-dien-3-one-21-carboxylicacid, γ-lactone (X-cis, EXAMPLE 7) for 1 hr., the reaction mixture isquenched with hydrochloric acid (5% aqueous, 25 ml) and stirred at20-25° for 20 min., at which time isomerization to trans is complete.The organic phase is then separated, concentrated, and flashchromatographed (silica gel, 150 g; gradient elution, 40%→70% ethylacetate/cyclohexane) to give the title compound. This material is thencrystallized from ethyl acetate/heptane (70/30) to give the titlecompound in pure form, CMR (100 MHz, CDCl₃) 199.25, 198.39, 176.41,166.79, 166.39, 149.00, 142.57, 125.67, 118.20, 113.11, 94.90, 47.75,44.40, 42.40, 40.45, ˜40, 35.63, 35.25, 34.01, 33.56, 32.73, 31.29,29.04, 27.14, 23.32, 20.47 and 13.98 δ; NMR (400 MHz, CDCl₃) 1.14,1.4-4.1, 1.61, 2.44, 5.75, 6.14 and 8.41 δ.

Example 917β-Hydroxy-7α-(2′-hydroperoxy-2′-methoxyacetyl)pregna-4,9(11)-dien-3-one-21-carboxylicacid, γ-lactone (IV-OOH)

A stream of ozone/oxygen is passed through a cooled (−78°) mixture of17β-hydroxy-7α-(trans-3′-acetoxyacryloyl)-pregna-4,9(11)-dien-3-one-21-carboxylicacid, γ-lactone (X-trans, EXAMPLE 8, 311.0 mg, 0.6872 mmoles) inmethylene/methanol (2/1, 6 ml) until a blue color persisted (3 min.).The excess ozone is purged with oxygen followed by nitrogen, then thereaction mixture is warmed to 20-25° and diluted with methylene chlorideto 10 ml. A portion of this mixture (3.5 ml, from 0.2405 mmolestrans-enolacetate) is concentrated to dryness to give the titlecompound.

Example 10 5α,17β-Dihydroxypregn-9(11)-ene-3-one 7α, 21-dicarboxylicacid, bis-γ-lactone (VII)

17β-Hydroxy-7α-(2′-hydroperoxy-2′-methoxyacetyl)pregna-4,9(11)-dien-3-one-21carboxylic acid, γ-lactone (IV-OOH, EXAMPLE 9, 3.5 ml, from 0.2405mmoles trans-enolacetate) is concentrated to dryness and the residuedissolved in trifluoroacetic acid (1.0 ml), stirred at 20-250 for 20min., then diluted with ethyl acetate (1.0 ml), washed with aqueoussodium bicarbonate, diluted with methylenechloride (2.0 ml), washed withdiluted aqueous hydrochloric acid and concentrated. The concentrate istaken up in methylene chloride (1.0 ml), stirred with aqueoushydrochloric acid 16N) for 30 min, then concentrated to give the titlecompound, CMR (100 MHz, CDCl₃) 206.39, 176.80, 175.59, 139.66, 124.11,95.12, 91.11, 47.14, 43.99, 42.45, 41.66, 41.63, 41.15, 39.01, 37.04,35.23, 33.08, 32.50, 31.42, 29.21, 23.16, 23.06 and 14.30 δ; NMR (400MHz, CDCl₃) 0.94, 1.40, 1.5-2.6, 2.80, 5.70 δ; MS (Cl, NH₃) m/e=402(100%, P+NH₄).

Example 1117β-Hydroxy-7α-(2′-oxo-acetyl)-pregna-4,9(11)-dien-3-one-21-carboxylicacid, γ-lactone (V)

A stream of ozone/oxygen is passed through a cooled (−790) mixture of17β-hydroxy-7α-(trans-1′,4′-dioxopent-2′-en-1′-yl)pregna-4,9-dien-3-one-21carboxylic acid, γ-lactone (III-trans, EXAMPLE 4B, 503.4 mg, 1.1531mmoles) in methylene chloride/methanol (1/1, 4.0 ml) until TLC analysis(acetone/methylene chloride, 317) indicates that conversion of startingmaterial (R_(f)=0.70) to a more polar product 4B, 0.45) is complete (10min.). The reaction mixture is then quenched with dimethylsulfide (0.20ml, 169 mg, 2.72 mmoles, 2.34 equivalents), stirred at 20-250 for 1 hr.,and then concentrated. The concentrate is flash chromatographed (silicagel, 60 g; gradient elution, acetone/methylene chloride 5%-25%) to givethe title compound, CMR (100 MHz, CD₃CN) 198.68, 197.54, 187.93, 176.09,166.40, 142.33, 125.02, 118.56, 94.44, ˜44, 42.49, 40.34, ˜40, 39.87,34.60, 33.83, 33.56, 33.32, 32.39, 30.53, 28.39, 26.16, 22.43 and 13.22δ; NMR (400 MHz, CD₃CN) 0.87, 1.37, 1.2-2.9, 5.49, 5.63 and 8.93 δ; MS(C₁, NH₃) m/e=397 (P+H, 100%).

Example 1211α,17β-Dihydroxy-7α-(5′-methyl-2′-furyl)-pregn-4-en-3-one-21-carboxylicacid, γ-lactone (II)

A mixture of 11α-hydroxycanrenone (I, 30.00 g, 84.1586 mmoles) innitromethane (240 ml) and methylene chloride (60 ml) is cooled to −20°then treated with 2-methylfuran (15.6 ml, 14.20 g, 0.1729 moles, 2.05equivalents) followed by ethanol (5.1 ml, 4.03 g, 87.454 mmoles, 1.04equivalents) followed by boron trifluoride diethyl etherate (BF₃—OEt₂,12.0 ml, 13.44 g, 94.695 mmoles, 1.13 equivalents). The reaction mixtureis stirred at −17° for 20 hrs., then quenched with ammonia (15% aqueous,60 ml), extracted with methylene chloride (120 ml), dried over sodiumsulfate (40 g) and concentrated. The concentrate is dissolved inmethylene chloride/ethyl acetate (1/1, 300 ml) concentrated to a volumeof 75 ml, diluted with 150 ml cyclohexane, concentrated to a volume of200 ml, and filtered to give the title compound, CMR (75 MHz, CDCl₃)199.59, 176.67, 170.11, 152.92, 150.28, 126.20, 108.67, 105.90, 95.18,68.55, 52.05, 45.84, 45.58, 43.08, 39.73, 38.62, 38.42, 37.47, 36.54,35.26, 34.17, 30.91, 29.05, 22.62, 18.40, 15.58 and 13.44 δ; NMR-(300MHz, CDCl₃) 1.01, 1.1-3.2, 1.41, 2.20, 4.12, 5.73, 5.83 and 5.93 δ.

The filtrate is concentrated. The concentrate is taken up in ethylacetate (30 ml warm), cooled to 10°, and filtered to give a second cropof crystal of the title-compound.

Example 1317β-Hydroxy-7α-(5′-methyl-2′-furyl)-pregna-4,9(11)-dien-3-one-21-carboxylicacid, γ-lactone (II)

A mixture of11α,17β-dihydroxy-7α-(5′-methyl-2′-furyl)-pregn-4-en-3-one-21-carboxylicacid, γ-lactone (II, EXAMPLE 12, 438.3 mg, 0.9994 mmoles) in THF (7.3ml) is cooled to −50°, then treated all at once with solid phosphorouspentachloride, (PCl₅, 287.5 mg, 1.381 mmoles, 1.38 equivalents). Afterstirring for 42 min., analysis by LC indicates that conversion to thetitle compound is complete. After another 21 min., the mixture isquenched with water (22 ml) and warmed to 20-25°. After 20 min., themixture is extracted with methylene chloride (2×15 ml), dried overmagnesium sulfate, and concentrated to give the title compound,identified by LC retention time comparison with a sample from EXAMPLE 3.

Example 149α,11α-Epoxy-17β-hydroxy-7α-(5′-methyl-2′-furyl)-pregn-4-en-3-one-21-carboxylicacid, γ-lactone (II)

A mixture of 9α,11α-epoxycanrenone (I, J. Med. Chem., 6, 732 (1963) andHelv. Chim. Acta 80, 566 (1997), 10.0135 g, 28.2508 mmoles) innitromethane (80 ml) and methylene chloride (20 ml) is cooled to −20°then treated with 2-methylfuran (5.10 ml, 4.64 g, 56.529 mmoles, 2.00equivalents) followed by ethanol (1.7 ml, 1.343 g, 29.151 mmoles, 1.03equivalents) followed by boron trifluoride diethyl etherate (BF₃OEt₂,3.6 ml, 4.03 g, 28.408 mmoles, 1.01 equivalents). The reaction mixtureis stirred at −20° for 24 hrs., at which time conversion to the productis complete as determined by LC, so the reaction is quenched withaqueous ammonia (15%, 10 ml), extracted with methylene chloride (2×100ml), and concentrated to a residue which is flash chromatographed (560 gsilica gel; gradient elution, 50%→90% ethyl acetate/cyclohexane). Thematerial obtained by chromatography is triturated with cyclohexane (100ml) at reflux for two hrs., then cooled to 0° and filtered to give thetitle compound, CMR (75 MHz, CDCl₃) 198.10, 176.26, 165.67, 153.19,149.96, 127.56, 107.92, 106.14, 94.66, 65.45, 49.92, 43.82, 40.00,39.18, 37.43, 37.37, 35.54, 35.00, 33.24, 31.00, 30.81, 28.91, 26.98,22.26, 22.00, 16.61 and 13.47 δ; NMR (300 MHz, CDCl₃) 1.02, 1.3-3.0,1.52, 2.20, 3.28, 5.85, 5.92 and 6.01 δ. The assigned structure isconfirmed by X-ray crystallography.

Example 15 17β-Hydroxypregna-4,9(11)-dien-3-one-7α,21-dicarboxylic acid,t lactone (VI) via direct ozonization of17β-hydroxy-7α-(cis-4′-oxo-pent-2′-enoyl)-3-oxo-pregna-4,9(11)-diene-21-carboxylicacid, γ-lactone (III-cis)

A stream of ozone/oxygen is passed through a cooled (−550) mixture of17β-hydroxy-7α-(cis-4′-oxo-pent-2′-enoyl)-pregna-4,9(11)-dien-3-one-21-carboxylicacid, γ-lactone (III-cis, EXAMPLE 4 Step A, 52.4 mg, 0.1200 mmoles) inmethylene chloride/isopropyl alcohol (1/1, 3.0 ml) containing water (50mg, 2.77 mmoles, 23.1 equivalents) until disappearance of startingmaterial is complete by LC (126 secs.). The reaction mixture is thenquenched with dimethylsulfide (0.033 ml, 27.9 mg, 0.449 mmoles, 3.74equivalents), stirred at 20-250 for 45 min., then diluted with methanol(5 ml), treated with aqueous hydrogen peroxide (70%, 50 μl, containing45.6 mg [1.34 mmoles, 11.2 equivalents] of hydrogen peroxide, treatedwith a mixture of potassium bicarbonate (62.4 mg, 0.623 mmoles, 5.19equivalents) in water (2 ml) and the resulting mixture stirred at20-25°. After 15 hrs, analysis by LC indicates formation of the titlecompound.

Example 16 17β-Hydroxypregna-4,9(11)-dien-3-one-7α, 21-dicarboxylicacid, γ-lactone (VI) via direct ozonization of17β-hydroxy-7α-trans-4′-oxo-pent-2′-enoyl)-pregna-4,9(11)-dien-3-one-21-carboxylicacid, γ-lactone (III-trans)

A stream of ozone/oxygen is passed through a cooled (−55°) mixture of17β-hydroxy-7α-(trans-4′-oxo-pent-2′-enoyl)-pregna-4,9(1)-dien-3-one-21-carboxylicacid, γ-lactone (III-trans, EXAMPLE 4 Step B, 103.5 mg, 0.2371 mmoles)in methylene chloride/isopropyl alcohol (1/1, 3 ml) containing water (50mg, 2.77 mmoles, 11.7 equivalents) until disappearance of startingmaterial is complete by LC (100 secs.). The reaction mixture is thenquenched with dimethylsulfide (CH₃SCH₃, 65 μl, 55.0 mg, 0.885 mmoles,3.73 equivalents), stirred at 20-25° for 45 min., then diluted to avolume of 10.0 ml with methanol. A 5.0 ml portion of this mixture istreated with aqueous hydrogen peroxide (70%, 50 μl, containing 45.6 mg[1.34 mmoles, 11.3 equivalents] of hydrogen peroxide, treated with amixture of potassium bicarbonate (59 mg, 0.589 mmoles, 4.97 equivalents)in water (2.1 ml), and the resulting mixture stirred at 20-25°. After 15hrs., analysis by LC (ESTD) indicates formation of the title compound,CMR (100 MHz, CDCl₃) 199.96, 177.42, 174.28, 169.06, 142.10, 124.86,118.60, 95.60, 44.23, 43.48, 42.61, 40.38, 39.79, 35.59, 35.08, 33.73,33.30, 32.57, 31.05, 28.98, 26.80, 22.92 and 13.68 δ; NMR (400 MHz,CDCl₃) 0.96, 1.42, 1.5-3.0, 4.28, 5.64 and 5.74 δ; MS (Cl, NH₃; m/e)=402(P+NH₄ ⁺).

Example 17 5α,17β-Dihydroxypregn-9(11)-ene-3-one 7α, 21-dicarboxylicacid, bis-γ-lactone, 3-dimethyl ketal (VII-ketal)

5α,17β-Dihydroxypregn-9(11)-ene-3-one 7α, 21-dicarboxylic acid,bis-γ-lactone (VII, EXAMPLE 10) is treated with at least one equivalentof trimethyl ortho formate in the presence of a catalytic amount ofp-toluenesulfonic acid by the procedure of International PublicationWO98/25948, to give the title compound.

Example 18 17β-hydroxypregna-4,9(11)-dien-3-one-7α,21-dicarboxylic acid,γ-lactone, methyl ester (VIII)

11α,17β-dihydroxypregn-4-en-3-one-7α,21-dicarboxylic acid, γ-lactone,methyl ester (VII, Drugs of the Future, 24(5), 488-501 (1999), compound(VI)), 5.00 g, 12.0 mmol) is mixed with acetonitrile (15 ml).N-(1,1,2,3,3,3)hexafluoropropyl)-diethylamine (V, 2.55 ml, 14.4 mmol) isadded to this the steroid mixture and heated to 600 for 2.5 hours. Theresulting mixture is cooled to 20-259 and the reaction is quenched withmethanol (100 L). A saturated aqueous solution of potassium bicarbonate(15 ml) is added. The acetonitrile is then removed under reducedpressure. The resulting mixture is extracted with methylene chloride(3×10 ml). The combined organic phases are washed with a aqueoussolution of sodium chloride (10%, 20 ml). The solvent is dried withmagnesium sulfate. The solvent is exchanged from methylene chloride tomethyl t-butyl ether (MTBE). The mixture is concentrated to a finalvolume of 25 ml. The resulting slurry is stirred overnight and the finalproduct, the title compound, is collected by filtration.

Example 19 17β-hydroxypregna-4,9(11)-dien-3-one-7α,21-dicarboxylic acid,γ-lactone, methyl ester (VIII)

11α,17β-dihydroxypregn-4-en-3-one-7α,21-dicarboxylic acid, γ-lactone,methyl ester (VIII, 5.00 g, 12.0 mmol) is placed in a flask withacetonitrile (15 ml). To this mixtureN-(1,1,2,3,3,3)hexafluoropropyl)-diethylamine (2.55 ml, 14.4 mmol) isadded and heated to 60° for 2 hrs. The mixture is cooled to 20-250 andthe reaction is quenched with aqueous potassium bicarbonate (20%solution, 18 ml). The acetonitrile is removed under reduced pressure,the aqueous layer is extracted with methylene chloride (3×5 ml). Thecombined organic phases are washed with sodium chloride solution (10%;10 ml). The solvent is exchanged from methylene chloride to methylisobutyl ketone/heptane to crystallize the title compound,mp=198.6-199.5°; MS (m/z) calculated for C₂₄H₃₀O₅=398.5 (M+), found398.9(M+); NMR (CDCl₃) 5.69, 5.64, 3.62, 2.97, 2.84-1.47, 1.38 and 0.93δ; CMR (CDCl₃) 98.5, 176.4, 172.5, 166.5, 142.3, 125.6, 118.9, 95.0,51.3, 43.0, 40.3, 35.6, 35.2, 34.1, 33.7, 32.8, 31.2, 29.0, 27.1, 23.2and 14.0 δ.

Example 20 17β-hydroxypregna-4,9(11)-dien-3-one-7α,21-dicarboxylic acid,e lactone, methyl ester (VIII)

11α,17β-dihydroxypregn-4-en-3-one-7α,21-dicarboxylic acid, γ-lactone,methyl ester (VIII, 80.00 g, 192.1 mmol) is placed in a flask withacetonitrile 80 ml). To this mixtureN-(1,1,2,3,3,3)hexafluoropropyl)-diethylamine (40.8 ml, 224.8 mmol) isadded and heated slowly to 45 to 50°, then held for 1-2 hours. Themixture is cooled to 20-25° and the reaction is quenched with aqueouspotassium bicarbonate (72 g in 288 ml). Methylene chloride (240 ml) isadded and after mixing the layers are separated. The aqueous phase isextracted with methylene chloride (100 ml). The combined organic phasesare washed with water (240 ml). The solvent is exchanged from methylenechloride to methyl tert-butyl ether, and branched octane is added dropwise to crystallize the product which is the title compound.

Example 2117β-Hydroxy-7α-(5′-methyl-2′-furyl)-pregna-4,9-dien-3-one-21-carboxylicacid, γ-lactone (II)

Following the general procedure of EXAMPLE 3, using the same reactantsand making non-critical variations, the title compound is obtained, CMR(100 MHz, CDCl₃) 198.56, 176.53, 167.45, 152.74, 149.99, 142.84, 126.24,119.73, 107.12, 105.89, 95.19, 44.08, 42.39, 41.90, 40.78, 38.52, 37.57,35.39, 34.18, 33.93, 32.93, 31.26, 29.14, 26.83, 23.18, 14.12 and 13.38δ; NMR (400 MHz, CDCl₃) 0.95, 1.43, 1.4-2.6, 2.16, 2.93 and 5.7 δ.

Example 2217β-Hydroxy-7α-(cis-1′,4′-dioxopent-2′-en-1′-yl)pregna-4,9-dien-3-one-21-carboxylicacid, γ-lactone (III-cis)

Following the general procedure of EXAMPLE 4, Step A, using the samereactants and making non-critical variations, the title compound isobtained,

CMR (100 MHz, CDCl₃) 202.28, ˜200, 199.05, 177.19, 166.65, 142.34,138.49, 134.39, 126.37, 119.90, 95.57, 49.63, 44.90, 42.39, 41.08,41.04, 35.82, 35.75, 34.49, 34.07, 33.25, 31.71, 30.12, 29.64, 27.49,23.76 and 14.34 δ; NMR (400 MHz, CDCl₃) 0.93, 1.40, 1.4-2.9, 2.24, 5.66,5.72, 6.15 and 6.28 δ.

Example 2317β-Hydroxy-7α-(2′-hydroperoxy-2′-methoxyacetyl)pregna-4,9(11)-dien-3-one-21-carboxylicacid, γ-lactone (IV-OOH)

Following the general procedure of EXAMPLE 9, using the same reactantsand making non-critical variations, the title compound is obtained, CMR(100 MHz, CDCl₃) 203.54, 199.91, 177.51, 168.98, 142.42, 125.05, 117.89,105.90, 95.58, 55.82, 44.21, 44.21, 42.17, 41.21, 40.37, 35.33, 34.84,33.62, 33.16, 32.38, 30.79, 28.84, 26.72, 23.02 and 13.55 δ; NMR (400MHz, CDCl₃) 0.94, 1.42, 1.4-2.8, 3.57, 4.34, 4.75 and 5.63 δ.

Example 2417β-Hydroxy-7α-(5′-methyl-2′-furyl)-pregna-4,9(11)-dien-3-one-21-carboxylicacid, γ-lactone (II)

A mixture of Δ⁹-canrenone (I, 105 g, 0.31024 moles) in acetonitrile (450ml) is treated with ethanol (21.0 g, 0.4558 moles, 1.47 equivalents),isopropanol (1.5 ml, 1.177 g, 19.592 mmoles, 0.063 equivalents) and2-methylfuran (48.5 g; 0.5907 moles, 1.90 equivalents), then cooled to−18° and treated with boron trifluoride diethyl etherate (63.0 g, 0.4439moles, 1.43 equivalents) over 4 hours. After stirring at 18° for 24hrs., the mixture is quenched with triethylamine (38.0 g, 0.3755 moles,1.21 equivalents) and concentrated to a thick slurry, which is dilutedwith water (350 ml), extracted with methylene chloride (400 ml), washedwith water (350 ml), then concentrated, n-propyl acetate added, andfurther concentrated to give a slurry, which is cooled to 0°, filtered,and the cake washed with n-propyl acetate/methyl-t-butyl ether (1/1)followed by methyl-t-butyl ether to give the title compound, identifiedby LC retention time comparison with a sample from EXAMPLE 3.

Example 25 5α,17β-Dihydroxypregn-9(11)-ene-3-one, 7α,21-dicarboxylicacid, bis-γ-lactone (VII)

A mixture of17β-hydroxy-7α-(5′-methyl-2′-furyl)-pregna-4,9(11)-dien-3-one-21-carboxylicacid, γ-lactone (II, EXAMPLE 24, 100 g, 0.23778 moles) and potassiumacetate (50.0 g, 0.5094 moles, 2.14 equivalents) in acetone (500 ml) andwater (150 ml) is cooled to −10° and treated with a slurry ofdibromantin (34.0 g, 0.1189 moles, 0.50 molar equivalents) in water (100ml) until a rise in the redox potential occurred. At this point, LCanalysis indicated complete conversion into enedione (III-cis). Thereaction mixture containing the enedione (III-cis) is then quenched withisobutyl vinyl ether (1.0 ml, 0.768 g, 7.668 mmoles, 0.032 equivalents),concentrated to a thick slurry, diluted with methylene chloride (200ml), and treated with 20° concentrated hydrochloric acid (50.0 ml, 0.50moles, 2.10 equivalents). The mixture is stirred at 20-25° for 2 hrs.,at which time LC analysis indicated complete conversion to enedione(III-trans). The organic phase containing the enedione (III-trans) isseparated, diluted with methylene chloride (80 ml) and methanol-(300ml), and cooled to 48°. A stream of O₃/O₂ is bubbled through thismixture until LC analysis indicated complete disappearance of theenedione (III-trans), then the mixture is quenched with dimethylsulfide(30.0 ml, 25.38 g, 0.4085 moles, 1.72 equivalents), stirred at −20° for16 hrs., concentrated to a volume of about 300 ml, diluted with methanol(350 ml), concentrated to a volume of about 300 ml, diluted withisopropanol (40 ml) and methanol (80 ml), then treated with a warm(55-60°) solution of potassium bicarbonate (120 g, 1.19986 moles, 5.04equivalents), in water (240 ml). This slurry is cooled to 5-10°, thenhydrogen peroxide (50%, 66.0 g, containing 33<) g (0.9703 moles, 4.08equivalents) hydrogen peroxide) is added over 3 hrs. The mixture isstirred for four hrs. and quenched with dimethylsulfide (40 ml, 33.84 g,0.5447 moles, 2.29 equivalents). After stirring at 20-25° for 23 hrs.,the mixture is diluted with methylene chloride (100 ml) and water (80ml), and acidified to pH=3.0 with concentrated hydrochloric acid. Thetwo-phase mixture is heated to 36°, then the phases are separated andthe aqueous phase extracted with methylene chloride (100 ml). Theorganic phases are combined, washed with water (75 ml), and the aqueousphase is back-extracted with methylene chloride (25 ml). The organicphases are combined, concentrated to a volume of 150 ml, then treatedwith benzenesulfonic acid (1.0 g of 90% pure material, containing 0.90 g(5.690 mmoles, 0.0239 equivalents) benzenesulfonic acid) and acetone (50ml). The mixture is then concentrated atmospherically to a volume of 160ml, then diluted with acetone (250 ml), concentrated to a volume of 200ml, cooled to 120, and filtered. The filter cake is washed with coldacetone (2×25 ml) and dried by nitrogen stream to give the titlecompound, CMR (100 MHz, CDCl₃) 206.08, 176.47, 175.41, 139.63, 124.00,94.89, 90.97, 47.08, 43.90, 42.36, 41.58, 41.07, 38.93, 36.97, 35.16,33.01, 32.42, 32.42, 31.35, 29.10, 23.08, 22.98 and 14.23 δ; NMR (400MHz, CDCl₃) 0.94, 1.40, 1.4-2.8 and 5.70; MS (C₁, NH₃) m/e=385 (P+H,100%).

Example 2617β-Hydroxy-7α-carbomethoxypregna-4,9(11)-dien-3-one-21-carboxylic acid,γ-lactone (VIII)

A mixture of 5α,17β-dihydroxypregn-9(11)-ene-3-one, 7α,21-dicarboxylicacid, bis-γ-lactone (VII, EXAMPLE 25, 50.0 g, 0.13005 moles) andpotassium bicarbonate (16.92 g, 0.1690 moles, 1.30 equivalents) inacetone (200 ml) and water (100 ml) is stirred at 45° for 2 hrs., atwhich time conversion of the 5,7-lactone (VII) into the carboxylic acid(VI) is complete by LC. The resulting mixture is then treated withdimethylsulfate (22.92 g, 0.1817 moles, 1.40 equivalents), stirred at45° for 3 hrs., then treated with a solution of potassium bicarbonate(1.3 g, 0.0130 moles, 0.100 equivalents) in water (10 ml) followed byneat triethylamine (1.81 ml, 1.314 g, 0.0130 moles, 0.100 equivalents).The mixture is stirred at 45° for 1 hr., quenched with concentratedhydrochloric acid (1.92 ml, 2.304 g, containing 0.852 g (0.234 moles,0.180 equivalents) hydrochloric acid), cooled to 0°, concentrated underreduced pressure to a volume of 150 ml (pot temperature 13°), thenfiltered and the filter cake is washed with water (2×25 ml) and dried togive the title compound, by comparison with an authentic sample by LC.

Example 2717β-Hydroxy-7α-(5′-t-butyl-2′-furyl)-pregna-4,9(11)-dien-3-the-21-carboxylicacid, γ-lactone (II)

A mixture of Δ⁹-canrenone (I, 3.0002 g, 8.8645 mmoles) and2-t-butylfuran (2.53 ml, 2.204 g, 17.745 mmoles, 2.00 equivalents) innitromethane (12.0 ml) is treated with ethanol (0.52 ml, 413 mg, 8.96mmoles, 1.01 equivalents), cooled to −20°, and treated with borontrifluoride diethyl etherate (1.24 ml, 1.389 g, 9.785 mmoles, 1.10equivalents). The resulting mixture is stirred at −20° for 24 hrs., thenat —5° for 12 hrs., then at 0° for 4 hrs., at which time the reactionappeared about 90% complete by TLC. The reaction is quenched withammonium hydroxide (7%, 30 ml) extracted with methylene chloride (3×50ml), dried over magnesium sulfate, and concentrated. The concentrate isflash chromatographed on (silica gel, 150 g; gradient elution, 10%→50%ethyl acetate/cyclohexane). The fractions containing pure product arecombined and concentrated to give the title compound, CMR (100 MHz,CDCl₃) 198.56, 176.53, 167.87, 162.48, 153.02, 142.91, 125.84, 119.42,106.70, 101.88, 95.21, 44.05, 42.87, 41.90, 40.84, 38.17, 37.80, 35.52,34.20, 34.02, 32.97, 32.40, 31.33, 29.18, 28.71, 26.79, 23.17 and 14.14δ; NMR (400 MHz, CDCl₃) 0.95, 1.16, 1.45, 1.5-2.6, 2.94, 3.30, 5.64,5.72 and 5.76 δ.

Example 2811α,17β-Dihydroxy-7α-(5′-t-butyl-2′-furyl)-pregn-4-en-3-one-21-carboxylicacid, γ-lactone (II)

A mixture of 11α-hydroxycanrenone (I, 2.03 g, 5.6947 mmoles) and2-t-butylfuran (1.70 ml, 1.481 g, 11.924 mmoles, 2.09 equivalents) innitromethane (16 ml) is cooled to −20°, treated with ethanol (0.35 ml,0.276 g, 5.99 mmoles, 1.05 equivalents) and boron trifluoride diethyletherate (0.83 ml, 0.930 g, 6.550 mmoles, 1.15 equivalents), and stirredat −20° for 21 hrs., at which time LC analysis indicates that thereaction is complete. The reaction mixture is then quenched withammonium hydroxide (15%, 5.5 ml), diluted with water, extracted withmethylene chloride (2×25 ml), dried over magnesium sulfate, filteredthrough 5.0 g magnesol, and concentrated to a foam, which is flashchromatographed (silica gel, 200 g; gradient elution 20%→70% ethylacetate/cyclohexane). The fractions containing the product are combinedand concentrated to give the title compound, UV λ_(max)=238 mμ.

Example 2911α,17β-Dihydroxy-7α-(4′-bromo-2′-furyl)-pregn-4-en-3-one-21-carboxylicacid, γ-lactone (II)

A mixture of 11α-hydroxycanrenone (I, 2.0 g, 5.6425 mmoles), ethyleneglycol (0.84 ml, 0.935 g, 15.06 mmoles, 2.67 equivalents), and3-bromofuran (3.0 ml, 4.905 g, 33.372 mmoles, 5.91 equivalents) innitromethane (32 ml) at 20-25° is treated with boron trifluoride diethyletherate (1.4 ml, 1.568 g, 11.048 mmoles, 1.96 equivalents) and stirredat 20-250 for 20 hrs., at which time the reaction is >80% complete byLC. The reaction is then quenched with water, extracted with ethylacetate, and concentrated to give a foam, which is dissolved inmethylene chloride (10 ml) and flash chromatographed silica gel, 150 g;gradient elution 0→6% isopropanol/methylene chloride). Theproduct-containing fractions are then combined and rechromatographed(silica gel, 100 g silica gel; gradient elution 0→6%isopropanol/methylene chloride). The product-containing fractions arecombined and crystallized from ethyl acetate/cyclohexane (112) to givethe title compound, CMR (100 MHz, CDCl₃) 199.77, 176.54, 168.67, 152.83,142.43, 126.05, 113.41, 98.03, 95.02, 69.19, 53.51, 46.26, 46.19, 43.40,39.57, 38.72, 38.05, 37.48, 35.39, 34.77, 34.24, 31.09, 29.11, 22.68,18.46 and 15.84 δ; NMR (400 MHz, CDCl₃) 0.9-2.9, 1.03, 1.42, 3.35, 4.11,6.36 and 726 δ; MS (Cl, NH₃) m/e=503, 505 (100%, P+H).

Example 3011α,17β-Dihydroxy-7α-(4′-methyl-2′-furyl)-pregn-4-en-3-one-21-carboxylicacid, γ-lactone (II)

A mixture of 11α-hydroxycanrenone (I, 816 mg, 2.2891 mmoles) and3-methylfuran (4.0 ml of 1.218 M solution in nitromethane, 4.87 mmoles,2.13 equivalents) in nitromethane (4.0 ml) is cooled to −20° and treatedwith ethylene glycol (0.168 ml, 187 mg 3.01 mmoles, 1.32 equivalents)followed by boron trifluoride diethyl etherate 0.284 ml, 318 mg, 2.241mmoles, 0.98 equivalents). The resulting mixture is stirred at −20° for−20 hrs., at which time the reaction is 86% complete by LC. The reactionmixture is quenched with aqueous ammonium hydroxide (15%, 4 ml) dilutedwith water (10 ml), extracted with methylene chloride (2×20 ml), driedover magnesium sulfate, and concentrated. The concentrate is flashchromatographed (silica gel, 60 g; gradient elution 50%-100% ethylacetate/cyclohexane). The product-containing fractions are combined andconcentrated. The concentrate is crystallized from cyclohexane/ethylacetate (4/1) to give the title compound, CMR (100 MHz, CDCl₃) 199.91,176.62, 170.02, 150.94, 140.81, 125.57, 115.27, 112.29, 95.07, 69.16,53.50, 46.13, 45.99, 43.24, 39.52, 39.46, 38.14, 37.35, 35.32, 34.18,31.05, 29.07, 22.28, 18.46, 15.79 and 10.21 δ; NMR (400 MHz, CDCl₃)1.04, 1.0-2.9, 1.42, 1.96, 3.14, 4.12, 5.34, 6.12 and 7.15 δ; MS (C₁,NH₃) m/e=439 (100%, P+H).

Example 3117β-Hydroxy-7α-(5′-methyl-2′-furyl)-pregna-4,9(11)-dien-3-one-21-carboxylicacid, γ-lactone (II)

Ishikawa reagent (2.4 mK, 13.7 mmol) is added to a mixture of11α,17β-dihydroxy-7α-(5′-methyl-2′-furyl)-pregn-4-en-3-one-21 carboxylicacid, γ-lactone (II, EXAMPLE 12, 5 g, 11.4 mmol) in acetonitrile (25mL). The mixture is heated to 600 and is determined complete in 1 hr byHPLC. The resulting mixture is cooled to 22° and quenched with saturatedaqueous sodium bicarbonate (15 mL). The organic solvent is removed underreduced pressure and replaced with methylene chloride (50 mL). Theorganic phase is separated, washed with water (30 mL) and concentratedto a volume of 20 mL. Water (30 mL) is added and the mixture isconcentrated to a volume of 20 mL. This water distillation is repeatedtwice to remove the N,N-diethyl-2,3,3,3-tetrafluoropriopionamideby-product. Then, methylene chloride (30 mL) is added to the resultingslurry to dissolve all solids. The organic layer is separated and thesolvent is exchanged to n-propyl acetate to a final volume of 17-18-mL.The resulting slurry is cooled to −20° for 12 hours. The product wascollected by filtration and dried under ambient nitrogen to give thetitle compound, mp=₁₉₈-203°; NMR (400 MHz, —CDCl₃), 5.737, 5.690, 3.300,2.904, 2.164, 1.431, 0.952 and 2.569-1.358 δ; CMR (100 MHz, CDCl₃)198.5, 176.5, 167.4, 152.7, 150.0, 142.8, 126.2, 119.7, 107.1, 105.9,95.2, 44.1, 42.4, 41.9, 38.5, 37.6, 35.4, 33.9, 32.9, 31.3, 29.1, 26.8,23.2, 14.1 and 13.4 δ; MS calculated for C₂₇H₃₃O₄=421.238 (M+H⁺),found=421.2 m/z.

Example 32 9α,11α-Epoxy-17β-hydroxypregn-4-en-3-one-7α,21-dicarboxylicacid, γ-lactone (VI)

A mixture of17β-hydroxy-7α-(2′-oxoacetyl)-pregna-4,9(11)-dien-3-one-21-carboxylicacid, γ-lactone (V, EXAMPLE 11, 6.7 mg, 0.0169 mmoles) in methylenechloride (40.5 ml) is treated with peracetic acid (35%, 4 μl, containing1.58 mg, 0.0208 mmoles, 1.23 equivalents of peracetic acid), stirred at20-25° for 25 hours, then treated with more peracetic acid (35%, 2 μl,containing 79 mg, 0.0104 mmoles, 0.62 equivalents of peracetic acid),then stirred at 20-25° for 49 hrs., at which time LC analysis indicatedconversion to the title compound, LC-UV (λ_(max)≈244 nm); LC-MS (m/e400).

Example 33 7α-Allyl-17β-hydroxypregna-4,9(11)-dien-3-one, 21-carboxylicacid, γ-lactone (II)

A mixture of 17β-hydroxypregna-4,6,9(11)-trien-3-one-21-carboxylic acid,γ-lactone (I, 1.0171 g, 3.0052 mmoles) in methylene chloride (62 ml) iscooled to −30° and treated with titanium tetrachloride in methylenechloride (1.0 M, 15.0 ml, 15.0 mmoles, 4.99 equivalents). The resultingmixture is treated with allyltrimethylsilane (3.0 ml, 2.16 g, 18.876mmoles, 6.28 equivalents) and stirred at −30° for 4 hrs., at which timeconversion of the starting material into the product (R_(f)=0.27) isnearly complete by TLC (ethyl acetate/cyclohexane, 35165). The reactionmixture is quenched with water (25 ml), extracted with methylenechloride (3×25 ml), and concentrated. The concentrate (weight=1.6262 g)is hash chromatographed (silica gel, 150 g; gradient elution with ethylacetate/cyclohexane, 15%→55%). The fractions containing the more polarproduct (R_(f)=0.27) are combined and concentrated to give the titlecompound, UV λ_(max)=241 nm; CMR (100 MHz, CDCl₃) 198.65, 176.46,167.31, 143.22, 136.36, 126.51, 119.84, 116.80, 95.22, 44.15, 42.50,41.13, 40.73, 37.33, 35.56, 35.43, 34.13, 33.78, 33.05, 31.65, 31.37,29.14, 26.86, 23.04, and 13.78 δ; NMR (400 MHz, CDCl₃) 0.94, 1.37,1.4-2.6, 4.95, 5.01, 5.65 and 5.74 b; MS (C₁, NH₃), m/e=381 (P+H, 100%);

The product is rechromatographed (silica gel, 60 g; gradient elutionwith ethyl acetate/cyclohexane, 15%→45%) to remove a more polar impurity(R_(f)=0.06). The product containing fractions are combined andconcentrated. A portion of the residue (96.8 mg) is taken up inmethylene chloride (1 ml), diluted with ethyl acetate (2 ml),concentrated to a volume of less than 1 ml, and cooled to 0°. Thesupernatant is decanted and the crystals recrystallized from ethylacetate at 0°. An X-ray crystallographic study confirmed the assignmentas 7α-allyl-17β-hydroxypregna-4,9(11)-dien-3-one, 21-carboxylic acid,γ-lactone.

Example 34 5α,17β-Dihydroxypregn-9(11)-ene-3-one, 7α,21-dicarboxylicacid, bis-γ-lactone (VII)

Step (1)-17β-Hydroxypregna-4,9(11)-dien-3-one-7α,21-dicarboxylic acid,γlactone (VI)

A mixture of17β-hydroxy-7α-(5′-methyl-2′-furyl)-pregna-4,9(11)-dien-3-one-21-carboxylicacid, γ-lactone (II, EXAMPLE 3, 20 g, 47.5568 mmoles) in methanol (60ml) and methylene chloride (60 ml) is cooled to −55°. Ozone in oxygen isbubbled through this mixture until 0.8 area % (by LC) of startingmaterial (II) remains. The mixture is purged of ozone by sparging withnitrogen and then quenched with dimethylsulfide (16 ml, 13.5 g, 217.9mmoles, 4.58 equivalents), warmed to 20-25°, stirred at 20-25° for 50min. The resulting mixture is concentrated to 80 ml, methanol (25 ml) isadded, and concentrated to 80 ml again. The mixture is then treated, at5°, with a solution of potassium bicarbonate (21.6 g; 215.7 mmoles; 4.54equivalents) in water (44 ml) followed by hydrogen peroxide (50%aqueous, 23.5 g, containing 11.75 g (345.5 mmoles, 7.27 equivalents) ofhydrogen peroxide). After warming to 20-30° for one hour the mixture isquenched with dimethylsulfide (8 ml, 6.75 g, 108.95 mmoles, 2.29equivalents). Methylene chloride (20 ml) is added, and the pH adjustedto 3 with hydrogen chloride (31.5% aqueous, 26.0 g containing8.199(224.4 mmoles; 4.72 equivalents) of hydrogen chloride. The mixtureis warmed to dissolve and the phases separated. The upper aqueous phaseis extracted with methylene chloride (10 ml) and the combined organicphases are extracted with water (10 ml.). LC was performed on themethylene chloride mixture (after aqueous workup) under the followingconditions:

-   -   Column: Supelco Discovery RP Amide C16; 5μ; 250 mm×4 mm    -   Flow: 1 ml/min    -   Detection: UV; 240 nm    -   Mobile Phase: A: 950 g Water; 39 g Acetonitrile; 1.0 g        Trifluoroacetic acid        -   B: 754 g Acetonitrile; 39 g Water; 1.0 g Trifluoroacetic            acid    -   Gradient: T₀: 80% A/20% B        -   T₁₅: 20% A/80% B        -   T_(15.1): 80% A/20% B        -   T₂₀: 80% A/20% B    -   Run Time: 20 minutes    -   Flow: 1 ml/min    -   Injection Volume: 5 λ    -   Sample Prep: 5 λ or reaction mixture into 1 ml of 1/1        Acetonitrile: phosphate buffer (1 ml phosphoric acid in 1 l        water; pH to 2.4 with sodium hydroxide)        The reaction LC major peak (72 area %) was at 10.52 minutes;        retention time of a known standard of the carboxylic acid (VI)        is 10.52 minutes.        Step (2)-5α,17β-Dihydroxypregn-9(11)-ene-3-one,        7α,21-dicarboxylic acid, bis-γ-lactone (VII)

The resulting organic phase containing17β-hydroxypregna-4,9(11)-dien-3-one-7α,21-dicarboxylic acid, γ-lactone(VI) is concentrated to 40 ml and para-toluene sulfonic acid monohydrate(10 mg; 0.042 mmoles; 0.001 equivalents) dissolved in acetone (15 ml) isadded. Crystallization is observed after 30 minutes at reflux. Theresulting slurry is concentrated to 50 ml and concentration continuedwhile maintaining a constant volume by the addition of fresh acetone.After 80 ml of acetone has been added the slurry is cooled to 0° and thesolids collected by filtration to give the title compound, CMR (100 MHz,CDCl₃) 206.07, 176.44, 175.41, 139.66, 123.98, 94.88, 90.99, 47.09,43.91, 42.36, 41.57, 41.08, 38.93, 36.98, 35.17, 33.01, 32.44, 31.36,29.10, 23.08, 22.99 and 14.24 δ; NMR (400 MHz, CDCl₃) 0.94, 1.41,1.5-2.6, 2.80 and 5.70 δ.

Example 35 17β-hydroxypregna-4,9(11)-dien-3-one-7α,21-dicarboxylic acid,γ-lactone, methyl ester (CII)

11α,17β-dihydroxypregn-4-en-3-one-7α,21-dicarboxylic acid, γ-lactone,methyl ester (Cl, Drugs of the Future, 24(5), 488-501 (1999), compound(VI) and International Publication WO98/25948, pages 76 and 280; 5.00 g,12.0 mmol) is mixed with acetonitrile (15 ml).N-(1,1,2,3,3,3)hexafluoropropyl)-diethylamine (CVI, 2.55 ml, 14.4 mmol)is added to this the steroid mixture and heated to 600 for 2.5 hours.The resulting mixture is cooled to 20-25° and the reaction is quenchedwith methanol (100 μL). A saturated aqueous solution of potassiumbicarbonate (15 ml) is added. The acetonitrile is then removed underreduced pressure. The resulting mixture is extracted with methylenechloride (3×10 ml). The combined organic phases are washed with aaqueous solution of sodium chloride (10%, 20 ml). The solvent is driedwith magnesium sulfate. The solvent is exchanged from methylene chlorideto methyl t-butyl ether (MTBE). The mixture is concentrated to a finalvolume of 25 ml. The resulting slurry is stirred overnight and the finalproduct, the title compound, is collected by filtration.

Example 36 17β-hydroxypregna-4,9(11)-dien-3-one-7α,21-dicarboxylic acid,γ-lactone, methyl ester (CII)

11α,17β-dihydroxypregn-4-en-3-one-7α,21-dicarboxylic acid, γ-lactone,methylester (Cl, 5.00 g, 12.0 mmol) is placed in a flask withacetonitrile (15 ml). To this mixture the Ishikawa reagent (2.55 ml,14.4 mmol) is added and heated to 60° for 2 hrs. The mixture is cooledto 20-25° and the reaction is quenched with aqueous potassiumbicarbonate (20% solution, 18 ml). The acetonitrile is removed underreduced pressure, the aqueous layer is extracted with methylene chloride(3×5 ml). The combined organic phases are washed with sodium chloridesolution (10%, 10 ml). The solvent is exchanged from methylene chlorideto methyl isobutyl ketone/heptane to crystallize the title compound,mp=198.6-199.5°; MS (m/z) calculated for C₂₄H₃₀O₅=398.5 (M+), found398.9(M+); NMR (CDCl₃) 5.69, 5.64, 3.62, 2.97, 2.84-1.47, 1.38 and 0.93δ; CMR (CDCl₃) 98.5, 176.4, 172.5, 166.5, 142.3, 125.6, 118.9, 95.0,51.3, 43.0, 40.3, 35.6, 35.2, 34.1, 33.7, 32.8, 31.2, 29.0, 27.1, 23.2and 14.0 δ.

Example 37 17β-hydroxypregna-4,9(11)-dien-3-one-7α,21-dicarboxylic acid,γ-lactone, methyl ester (CII)

11α,17β-dihydroxypregn-4-en-3-one-7α,21-dicarboxylic acid % lactone,methyl aster (Cl, 80.00 g, 192.1 mmol) is placed in a flask withacetonitrile (80 ml). To this mixture the Ishikawa reagent (40.8 ml,224.8 mmol) is added and heated slowly to 45 to 500, then held for 1-2hours. The mixture is cooled to 20-25° and the reaction is quenched withaqueous potassium bicarbonate (72 g in 288 ml). Methylene chloride (240ml) is added and after mixing the layers are separated. The aqueousphase is extracted with methylene chloride (100 ml). The combinedorganic phases are washed with water (4240 ml). The solvent is exchangedfrom methylene chloride to methyl tert-butyl ether, and branched octaneis added drop wise to crystallize the product which is the titlecompound.

Example 38 17β-hydroxypregna-4,9(11)-dien-3-one-70,21-dicarboxylic acid,Y lactone, methyl ester (CII)

11α,17β-dihydroxypregn-4-en-3-one-7α,21-dicarboxylic acid, γ-lactone,methyl ester (Cl, 80.00 g, 192.1 mmol) is placed in a flask withacetonitrile (80 ml). To this mixture the Ishikawa reagent (40.8 ml,224.8 mmol) is added and heated slowly to 55 to 50°, then held for 1-2hours. The mixture is cooled to 20-25° and the reaction is quenched withaqueous potassium bicarbonate (37.3 g in 288 ml). Methylene chloride(240 ml) is added and after, mixing the layers are separated. Theaqueous phase is extracted with methylenechloride (100 ml). The combinedorganic phases are washed with water (80 ml). The solvent is exchangedfrom methylene chloride to methyl isobutyl ketone, and branched octaneis added drop wise to crystallize the product which is the titlecompound.

1. A compound having the structure:

wherein: R_(b) is selected from the group consisting of —H, C₁-C₄ alkyl,and phenyl optionally substituted with one or two C₁-C₄ alkyl or C₁-C₄alkoxy; and R₇₋₂ is selected from the group consisting of —H and C₁-C₄alkyl optionally substituted with one or two —OH.
 2. The compound ofclaim 1 wherein R_(b) is —H.
 3. The compound of claim 1 wherein R₇₋₂ is—H.
 4. The compound of claim 1 wherein R₇₋₂ is methyl.
 5. The compoundof claim 1 wherein R₇₋₂ is isopropyl.
 6. The compound of claim 1 havingthe structure:


7. The compound of claim 1 having the structure


8. A compound having the structure:

wherein: R_(b) is selected from the group consisting of —H, C₁-C₄ alkyl,and phenyl optionally substituted with one or two C₁-C₄ alkyl or C₁-C₄alkoxy; and R₇₋₂ is selected from the group consisting of —H and C₁-C₄alkyl optionally substituted with one or two —OH.
 9. The compound ofclaim 8 wherein R_(b) is —H.
 10. The compound of claim 8 wherein R₇₋₂ is—H.
 11. The compound of claim 8 wherein R₇₋₂ is methyl.
 12. The compoundof claim 8 wherein R₇₋₂ is isopropyl.
 13. The compound of claim 8 havingthe structure:


14. A compound having the structure:

wherein: R_(b) is selected from the group consisting of —H, C₁-C₄ alkyl,and phenyl optionally substituted with one or two C₁-C₄ alkyl or C₁-C₄alkoxy; and R₇₋₂ is selected from the group consisting of —H and C₁-C₄alkyl optionally substituted with one or two —OH.
 15. The compound ofclaim 14 wherein R_(b) is —H.
 16. The compound of claim 14 wherein R₇₋₂is —H.
 17. The compound of claim 14 wherein R₇₋₂ is methyl.
 18. Thecompound of claim 14 wherein R₇₋₂ is isopropyl.
 19. The compound ofclaim 14 having the structure: